Редактирование: BRCA1

Breast cancer type 1 susceptibility protein (EC 2.3.2.27) (RING finger protein 53) (RING-type E3 ubiquitin transferase BRCA1) [RNF53]

==Publications==

{{medline-entry
|title=Babam2 Regulates Cell Cycle Progression and Pluripotency in Mouse Embryonic Stem Cells as Revealed by Induced DNA Damage.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33050379
|abstract=BRISC and [[BRCA1]]-A complex member 2 ([i]Babam2[/i]) plays an essential role in promoting cell cycle progression and preventing cellular senescence. [i]Babam2[/i]-deficient fibroblasts show proliferation defect and premature senescence compared with their wild-type (WT) counterpart. Pluripotent mouse embryonic stem cells (mESCs) are known to have unlimited cell proliferation and self-renewal capability without entering cellular senescence. Therefore, studying the role of [i]Babam2[/i] in ESCs would enable us to understand the mechanism of [i]Babam2[/i] in cellular aging, cell cycle regulation, and pluripotency in ESCs. For this study, we generated [i]Babam2[/i] knockout ([i]Babam2[/i] ) mESCs to investigate the function of [i]Babam2[/i] in mESCs. We demonstrated that the loss of [i]Babam2[/i] in mESCs leads to abnormal G1 phase retention in response to DNA damage induced by gamma irradiation or doxorubicin treatments. Key cell cycle regulators, [[CDC25A]] and [[CDK2]], were found to be degraded in [i]Babam2[/i]  mESCs following gamma irradiation. In addition, [i]Babam2[/i]  mESCs expressed p53 strongly and significantly longer than in control mESCs, where p53 inhibited Nanog expression and G1/S cell cycle progression. The combined effects significantly reduced developmental pluripotency in [i]Babam2[/i]  mESCs. In summary, [i]Babam2[/i] maintains cell cycle regulation and pluripotency in mESCs in response to induced DNA damage.

|keywords=* Babam2
* DNA damage
* cell cycle
* embryonic stem cells
* pluripotency
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600899
}}
{{medline-entry
|title=Declining BRCA-Mediated DNA Repair in Sperm Aging and its Prevention by Sphingosine-1-Phosphate.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31916095
|abstract=Recent data suggest that paternal age can have major impact on reproductive outcomes, and with increased age, there is increased likelihood of chromosomal abnormalities in the sperm. Here, we studied DNA damage and repair as a function of male aging and assessed whether sphingosine-1-phosphate (S1P), a ceramide-induced death inhibitor, can prevent sperm aging by enhancing DNA double-strand breaks (DSB) repair. We observed a significant increase in DNA damage with age and this increase was associated with a decline in the expression of key DNA DSB repair genes in mouse sperm. The haploinsufficiency of [[BRCA1]] male mice sperm showed significantly increased DNA damage and apoptosis, along with decreased chromatin integrity when compared to similar age wild type (WT) mice. Furthermore, haploinsufficiency of [[BRCA1]] male mice had lower sperm count and smaller litter size when crossed with WT females. The resulting embryos had a higher probability of growth arrest and reduced implantation. S1P treatment decreased genotoxic-stress-induced DNA damage in sperm and enhanced the expressions of key DNA repair genes such as [[BRCA1]]. Co-treatment with an [[ATM]] inhibitor reversed the effects of S1P, implying that the impact of S1P on DNA repair is via the [[ATM]]-mediated pathway. Our findings indicate a key role for DNA damage repair mechanism in the maintenance of sperm integrity and suggest that S1P can improve DNA repair in sperm. Further translational studies are warranted to determine the clinical significance of these findings and whether S1P can delay male reproductive aging. There is mounting evidence that sperm quality declines with age, similar to that of the oocyte. However, the reasons behind this decline are poorly understood and there is no medical intervention to improve sperm quality. Our study suggests a strong role for DNA damage repair in maintenance of sperm quality, and for the first time, a potential pharmaceutical approach to prevent sperm aging.

|keywords=* Aging
* DNA fragmentation
* Gene expression
* Sperm
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065969
}}
{{medline-entry
|title=BRCA-related [[ATM]]-mediated DNA double-strand break repair and ovarian aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31822904
|abstract=Oocyte aging has significant clinical consequences, and yet no treatment exists to address the age-related decline in oocyte quality. The lack of progress in the treatment of oocyte aging is due to the fact that the underlying molecular mechanisms are not sufficiently understood. [[BRCA1]] and 2 are involved in homologous DNA recombination and play essential roles in ataxia telangiectasia mutated ([[ATM]])-mediated DNA double-strand break (DSB) repair. A growing body of laboratory, translational and clinical evidence has emerged within the past decade indicating a role for BRCA function and [[ATM]]-mediated DNA DSB repair in ovarian aging. Although there are several competing or complementary theories, given the growing evidence tying BRCA function and [[ATM]]-mediated DNA DSB repair mechanisms in general to ovarian aging, we performed this review encompassing basic, translational and clinical work to assess the current state of knowledge on the topic. A clear understanding of the mechanisms underlying oocyte aging may result in targeted treatments to preserve ovarian reserve and improve oocyte quality. We searched for published articles in the PubMed database containing key words, BRCA, [[BRCA1]], [[BRCA2]], Mutations, Fertility, Ovarian Reserve, Infertility, Mechanisms of Ovarian Aging, Oocyte or Oocyte DNA Repair, in the English-language literature until May 2019. We did not include abstracts or conference proceedings, with the exception of our own. Laboratory studies provided robust and reproducible evidence that [[BRCA1]] function and [[ATM]]-mediated DNA DSB repair, in general, weakens with age in oocytes of multiple species including human. In both women with BRCA mutations and BRCA-mutant mice, primordial follicle numbers are reduced and there is accelerated accumulation of DNA DSBs in oocytes. In general, women with [[BRCA1]] mutations have lower ovarian reserves and experience earlier menopause. Laboratory evidence also supports critical role for [[BRCA1]] and other [[ATM]]-mediated DNA DSB repair pathway members in meiotic function. When laboratory, translational and clinical evidence is considered together, BRCA-related [[ATM]]-mediated DNA DSB repair function emerges as a likely regulator of ovarian aging. Moreover, DNA damage and repair appear to be key features in chemotherapy-induced ovarian aging. The existing data suggest that the BRCA-related [[ATM]]-mediated DNA repair pathway is a strong candidate to be a regulator of oocyte aging, and the age-related decline of this pathway likely impairs oocyte health. This knowledge may create an opportunity to develop targeted treatments to reverse or prevent physiological or chemotherapy-induced oocyte aging. On the immediate practical side, women with BRCA or similar mutations may need to be specially counselled for fertility preservation.
|mesh-terms=* Aging
* Animals
* Ataxia Telangiectasia
* BRCA1 Protein
* BRCA2 Protein
* DNA Breaks, Double-Stranded
* DNA Repair
* Female
* Fertility
* Fertility Preservation
* Humans
* Mice
* Oocytes
* Ovarian Follicle
* Ovarian Reserve
* Ovary
|keywords=* 
          BRCA
        
* 
          BRCA1/2
        
* DNA repair
* anti-Mullerian hormone
* chemotherapy
* mutations
* oocyte
* ovarian aging
* ovarian reserve
* ovarian response
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935693
}}
{{medline-entry
|title=The [[RXFP3]] receptor is functionally associated with cellular responses to oxidative stress and DNA damage.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31794429
|abstract=DNA damage response (DDR) processes, often caused by oxidative stress, are important in aging and -related disorders. We recently showed that G protein-coupled receptor (GPCR) kinase interacting protein 2 ([[GIT2]]) plays a key role in both DNA damage and oxidative stress. Multiple tissue analyses in [[GIT2]]KO mice demonstrated that [[GIT2]] expression affects the GPCR relaxin family peptide 3 receptor ([[RXFP3]]), and is thus a therapeutically-targetable system. [[RXFP3]] and [[GIT2]] play similar roles in metabolic aging processes. Gaining a detailed understanding of the [[RXFP3]]-[[GIT2]] functional relationship could aid the development of novel anti-aging therapies. We determined the connection between [[RXFP3]] and [[GIT2]] by investigating the role of [[RXFP3]] in oxidative stress and DDR. Analyzing the effects of oxidizing (H O ) and DNA-damaging (camptothecin) stressors on the interacting partners of [[RXFP3]] using Affinity Purification-Mass Spectrometry, we found multiple proteins linked to DDR and cell cycle control. [[RXFP3]] expression increased in response to DNA damage, overexpression, and Relaxin 3-mediated stimulation of [[RXFP3]] reduced phosphorylation of DNA damage marker [[H2AX]], and repair protein [[BRCA1]], moderating DNA damage. Our data suggests an [[RXFP3]]-[[GIT2]] system that could regulate cellular degradation after DNA damage, and could be a novel mechanism for mitigating the rate of age-related damage accumulation.
|mesh-terms=* Camptothecin
* Computational Biology
* DNA Damage
* Felodipine
* GTPase-Activating Proteins
* Gene Expression Regulation
* Gene Regulatory Networks
* HEK293 Cells
* Humans
* Oxidative Stress
* RNA, Messenger
* Receptors, G-Protein-Coupled
* Topoisomerase I Inhibitors
|keywords=* DNA damage
* GPCR
* aging
* relaxin 3
* relaxin family peptide 3 receptor
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6932917
}}
{{medline-entry
|title=Do [[BRCA1]] and [[BRCA2]] gene mutation carriers have a reduced ovarian reserve? Protocol for a prospective observational study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31772111
|abstract=[[BRCA1]]/2 gene mutations increase risk of breast and/or ovarian cancer and may have implications for reproductive health. Indirect biomarkers of the ovarian primordial follicle pool (anti-Müllerian hormone ([[AMH]])) and one small study in female cadavers suggest that ovarian reserve may be reduced in BRCA mutation carriers, but findings are conflicting and association between circulating [[AMH]] and primordial follicle number is not established. The aim of this study is to measure primordial follicle density in premenopausal ovarian tissue samples from women with [[BRCA1]]/2 gene mutations versus age-matched comparison group. Prospective observational study measuring associations between BRCA gene mutation status, premenopausal ovarian primordial follicle density and serum [[AMH]] concentrations versus age-matched premenopausal women from the general population. Primordial follicle density will be measured in cortical sections from ovarian tissue collected at the time of risk-reducing bilateral salpingo-oophorectomy (RRBSO) in 88 [[BRCA1]] gene mutation carriers, 65 [[BRCA2]] gene mutation carriers and 157 non-mutation carriers. Primordial follicle density will be determined by counting follicles in a known volume of ovarian cortical tissue using light microscopy. Follicles will be identified by immunohistochemical staining for oocyte marker mouse vasa homologue. To inform the mechanisms underlying reduced ovarian reserve, the proportion of follicles containing oocytes with DNA damage will be determined by immunohistochemical staining for phosphorylated histone [[H2AX]] and terminal deoxynucleotidyl transferase dUTP nick end labelling assay to identify apoptotic cells. Follicle density will be correlated with circulating [[AMH]] concentrations quantified in the same cohort, using an electrochemiluminescence immunoassay on an automated platform. Ethics approval has been granted by Peter MacCallum Cancer Centre to access biobanks, including; The Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab-HREC#97_27) and the What Happens after Menopause? (HREC12PMCC24-12/90) and Melbourne IVF.
|mesh-terms=* Adolescent
* Adult
* Aging
* BRCA1 Protein
* BRCA2 Protein
* Female
* Germ-Line Mutation
* Heterozygote
* Humans
* Immunohistochemistry
* Middle Aged
* Observational Studies as Topic
* Ovarian Follicle
* Ovarian Reserve
* Prospective Studies
* Research Design
* Young Adult
|keywords=* BRCA
* DNA repair
* fertility
* follicle
* germline mutation
* oocyte
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6887091
}}
{{medline-entry
|title=53BP1 Enforces Distinct Pre- and Post-resection Blocks on Homologous Recombination.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31653568
|abstract=53BP1 activity drives genome instability and lethality in [[BRCA1]]-deficient mice by inhibiting homologous recombination ([[HR]]). The anti-recombinogenic functions of 53BP1 require phosphorylation-dependent interactions with PTIP and [[RIF1]]/shieldin effector complexes. While [[RIF1]]/shieldin blocks 5'-3' nucleolytic processing of DNA ends, it remains unclear how PTIP antagonizes [[HR]]. Here, we show that mutation of the PTIP interaction site in 53BP1 (S25A) allows sufficient [[DNA2]]-dependent end resection to rescue the lethality of [[BRCA1]]  mice, despite increasing [[RIF1]] "end-blocking" at DNA damage sites. However, double-mutant cells fail to complete [[HR]], as excessive shieldin activity also inhibits [[RNF168]]-mediated loading of [[PALB2]]/[[RAD51]]. As a result, [[BRCA1]] 53BP1  mice exhibit hallmark features of [[HR]] insufficiency, including premature aging and hypersensitivity to PARPi. Disruption of shieldin or forced targeting of [[PALB2]] to ssDNA in [[BRCA1]] 53BP1  cells restores [[RNF168]] recruitment, [[RAD51]] nucleofilament formation, and PARPi resistance. Our study therefore reveals a critical function of shieldin post-resection that limits the loading of [[RAD51]].
|mesh-terms=* Aging
* Animals
* BRCA1 Protein
* DNA Breaks, Double-Stranded
* DNA Damage
* Genomic Instability
* Homologous Recombination
* Mice
* Mutation
* Poly(ADP-ribose) Polymerase Inhibitors
* Rad51 Recombinase
* Tumor Suppressor p53-Binding Protein 1
* Ubiquitin-Protein Ligases
|keywords=* 53BP1
* BRCA1
* PARPi
* aging
* cancer
* homologous recombination
* resection
* shieldin
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993210
}}
{{medline-entry
|title=Epigenome-wide exploratory study of monozygotic twins suggests differentially methylated regions to associate with hand grip strength.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31254144
|abstract=Hand grip strength is a measure of muscular strength and is used to study age-related loss of physical capacity. In order to explore the biological mechanisms that influence hand grip strength variation, an epigenome-wide association study (EWAS) of hand grip strength in 672 middle-aged and elderly monozygotic twins (age 55-90 years) was performed, using both individual and twin pair level analyses, the latter controlling the influence of genetic variation. Moreover, as measurements of hand grip strength performed over 8 years were available in the elderly twins (age 73-90 at intake), a longitudinal EWAS was conducted for this subsample. No genome-wide significant CpG sites or pathways were found, however two of the suggestive top CpG sites were mapped to the [[COL6A1]] and [[CACNA1B]] genes, known to be related to muscular dysfunction. By investigating genomic regions using the comb-p algorithm, several differentially methylated regions in regulatory domains were identified as significantly associated to hand grip strength, and pathway analyses of these regions revealed significant pathways related to the immune system, autoimmune disorders, including diabetes type 1 and viral myocarditis, as well as negative regulation of cell differentiation. The genes contributing to the immunological pathways were [[HLA-B]], [[HLA-C]], [[HLA-DMA]], [[HLA-DPB1]], [[MYH10]], [[ERAP1]] and [[IRF8]], while the genes implicated in the negative regulation of cell differentiation were [[IRF8]], [[CEBPD]], [[ID2]] and [[BRCA1]]. In conclusion, this exploratory study suggests hand grip strength to associate with differentially methylated regions enriched in immunological and cell differentiation pathways, and hence merits further investigations.
|mesh-terms=* Aged
* Aging
* Cell Differentiation
* CpG Islands
* Cross-Sectional Studies
* DNA Methylation
* Denmark
* Epigenesis, Genetic
* Epigenome
* Female
* Genome-Wide Association Study
* Hand Strength
* Humans
* Immunity
* Longitudinal Studies
* Male
* Middle Aged
* Twins, Monozygotic
|keywords=* Comb-p
* Epigenome-wide association study
* Hand grip strength
* Longitudinal data
* Pathway analyses
* Twin data
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6733812
}}
{{medline-entry
|title=[[PML]] nuclear bodies are recruited to persistent DNA damage lesions in an [[RNF168]]-53BP1 dependent manner and contribute to DNA repair.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31009828
|abstract=The bulk of DNA damage caused by ionizing radiation (IR) is generally repaired within hours, yet a subset of DNA lesions may persist even for long periods of time. Such persisting IR-induced foci (pIRIF) co-associate with [[PML]] nuclear bodies ([[PML]]-NBs) and are among the characteristics of cellular senescence. Here we addressed some fundamental questions concerning the nature and determinants of this co-association, the role of [[PML]]-NBs at such sites, and the reason for the persistence of DNA damage in human primary cells. We show that the persistent DNA lesions are devoid of homologous recombination ([[HR]]) proteins [[BRCA1]] and Rad51. Our super-resolution microscopy-based analysis showed that [[PML]]-NBs are juxtaposed to and partially overlap with the pIRIFs. Notably, depletion of 53BP1 resulted in decreased intersection between [[PML]]-NBs and pIRIFs implicating the [[RNF168]]-53BP1 pathway in their interaction. To test whether the formation and persistence of IRIFs is [[PML]]-dependent and to investigate the role of [[PML]] in the context of DNA repair and senescence, we genetically deleted [[PML]] in human hTERT-[[RPE]]-1 cells. Unexpectedly, upon high-dose IR treatment, cells displayed similar DNA damage signalling, repair dynamics and kinetics of cellular senescence regardless of the presence or absence of [[PML]]. In contrast, the [[PML]] knock-out cells showed increased sensitivity to low doses of IR and DNA-damaging agents mitomycin C, cisplatin and camptothecin that all cause DNA lesions requiring repair by [[HR]]. These results, along with enhanced sensitivity of the [[PML]] knock-out cells to DNA-PK and PARP inhibitors implicate [[PML]] as a factor contributing to [[HR]]-mediated DNA repair.
|mesh-terms=* Cellular Senescence
* DNA Damage
* DNA Repair
* Dose-Response Relationship, Radiation
* Gene Knockout Techniques
* Humans
* Intranuclear Inclusion Bodies
* Promyelocytic Leukemia Protein
* Tumor Suppressor p53-Binding Protein 1
* Ubiquitin-Protein Ligases
|keywords=* Cellular senescence
* DNA-PK and PARP/olaparib
* Homologous recombination
* Ionizing radiation
* Super-resolution microscopy
|full-text-url=https://sci-hub.do/10.1016/j.dnarep.2019.04.001
}}
{{medline-entry
|title=Mechanistic link between DNA damage sensing, repairing and signaling factors and immune signaling.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30798935
|abstract=Previously, DNA damage sensing, repairing and signaling machineries were thought to mainly suppress genomic instability in response to genotoxic stress. Emerging evidence indicates a crosstalk between DNA repair machinery and the immune system. In this chapter, we attempt to decipher the molecular choreography of how factors, including [[ATM]], [[BRCA1]], DNA-PK, FANCA/D2, [[MRE11]], [[MUS81]], NBS1, [[RAD51]] and [[TREX1]], of multiple DNA metabolic processes are directly or indirectly involved in suppressing cytosolic DNA sensing pathway-mediated immune signaling. We provide systematic details showing how different DDR factors' roles in modulating immune signaling are not direct, but are rather a consequence of their inherent ability to sense, repair and signal in response to DNA damage. Unexpectedly, most DDR factors negatively impact the immune system; that is, the immune system shows defective signaling if there are defects in DNA repair pathways. Thus, in addition to their known DNA repair and replication functions, DDR factors help prevent erroneous activation of immune signaling. A more precise understanding of the mechanisms by which different DDR factors function in immune signaling can be exploited to redirect the immune system for both preventing and treating autoimmunity, cellular senescence and cancer in humans.
|mesh-terms=* DNA
* DNA Damage
* DNA Repair
* Humans
* Signal Transduction
|keywords=* DDR
* Genomic instability
* Innate immunity
* MRE11
* Micronuclei
* NBS1
* RAD51
* STING
* Senescence
* cGAS
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7043287
}}
{{medline-entry
|title=Klotho gene polymorphisms are associated with healthy aging and longevity: Evidence from a meta-analysis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30633899
|abstract=Klotho gene polymorphisms have been implicated in healthy aging, but inconsistences in findings from previous case-control studies have raised concerns regarding the associations between KLOTHO gene polymorphisms and susceptibility to aging-related diseases and longevity. Hence, this meta-analysis was performed. We assessed the associations between two polymorphisms (G-395 A/rs1207568 and F352 V/rs9536314) and five parameters (urolithiasis, cognitive impairment, cardiovascular disease, cancer, and longevity) by calculating pooled odds ratios with 95% confidence intervals. According to the pooled results, the G allele of the G-395 A polymorphism conferred a significantly higher risk of urolithiasis; G-395 A was related to the susceptibility to cardiovascular disease under allele, dominant, and recessive models. There was no significant association between the G-395 A polymorphism and cognitive impairment among the elderly. The F allele of the F352 V polymorphism protected against breast and ovarian cancer susceptibility. Interestingly, based on the results of the subgroup analysis, the F352 V polymorphism was associated with the overall risk of neoplasms in [[BRCA1]] mutation carriers but not in [[BRCA2]] mutation carriers. Moreover, the F allele played a protective role in determining human longevity. In conclusion, Klotho G-395 A polymorphisms were associated with urolithiasis and cardiovascular disease but not with cognitive impairment. Additionally, Klotho F352 V polymorphisms were associated with cancers and longevity.
|mesh-terms=* Adult
* Aged
* Aged, 80 and over
* Aging
* Cardiovascular Diseases
* Case-Control Studies
* Cognitive Dysfunction
* Female
* Glucuronidase
* Healthy Aging
* Humans
* Longevity
* Male
* Middle Aged
* Neoplasms
* Polymorphism, Genetic
* Urolithiasis
|keywords=* Aging
* Gene polymorphisms
* Klotho
* Meta-Analysis
|full-text-url=https://sci-hub.do/10.1016/j.mad.2018.12.003
}}
{{medline-entry
|title=High expression of the breast cancer susceptibility gene [[BRCA1]] in long-lived termite kings.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30312170
|abstract=Aging is associated with the accumulation of DNA damage. High expression of DNA repair genes has been suggested to contribute to prolonged lifespan in several organisms. However, the crucial DNA repair genes contributing to longevity remain unknown. Termite kings have an extraordinary long lifespan compared with that of non-reproductive individuals such as workers despite being derived from the same genome, thus providing a singular model for identifying longevity-related genes. In this study, we demonstrated that termite kings express higher levels of the breast cancer susceptibility gene [[BRCA1]] than other castes. Using RNA sequencing, we identified 21 king-specific genes among 127 newly annotated DNA repair genes in the termite [i]Reticulitermes speratus[/i]. Using quantitative PCR, we revealed that some of the highly expressed king-specific genes were significantly upregulated in reproductive tissue (testis) compared to their expression in somatic tissue (fat body). Notably, [[BRCA1]] gene expression in the fat body was more than 4-fold higher in kings than in workers. These results suggest that [[BRCA1]] partly contributes to DNA repair in somatic and reproductive tissues in termite kings. These findings provide important insights into the linkage between [[BRCA1]] gene expression and the extraordinary lifespan of termite kings.
|mesh-terms=* Animals
* BRCA1 Protein
* DNA Repair
* Female
* Gene Expression Regulation
* Insect Proteins
* Isoptera
* Longevity
* Male
* Transcriptome
|keywords=* DNA repair
* gene expression
* lifespan
* social insects
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224230
}}
{{medline-entry
|title=The activated DNA double-strand break repair pathway in cumulus cells from aging patients may be used as a convincing predictor of poor outcomes after in vitro fertilization-embryo transfer treatment.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30235328
|abstract=Women with advanced maternal age exhibit low anti-Müllerian hormone (AMH) levels and an altered follicular environment, which is associated with poor oocyte quality and embryonic developmental potential. However, the underlying mechanism is poorly understood. The present study aimed to assesswhether aging patients exhibit an activated DNA double-strandbreak (DSB) repair pathway in cumulus cells and thus, an association with poor outcomes after in vitro fertilization-embryo transfer (IVF-ET) treatment. Cumulus cells from young (≤29 y) and aging (≥37 y) human female patients were collected after oocyte retrieval. Our results indicated that aging patients showed a higher rate of γ-[[H2AX]]-positive cells than in young patients (24.33±4.55 vs.12.40±2.31, P<0.05). We also found that the mRNA expression levels of [[BRCA1]], [[ATM]], [[MRE11]] and [[RAD51]] were significantly elevated in aging cumulus cells. Accordingly, significantly increased protein levels of phospho-[[H2AX]], [[BRCA1]], [[ATM]], [[MRE11]] and [[RAD51]] could be observed in aging cumulus cells. Moreover, aging cumulus cells showed a more frequent occurrence of early apoptosis than young cumulus cells. This study found that increases in DSBs and the activation of the repair pathway are potential indicators that may be used to predictoutcomes after IVF-ET treatment.
|mesh-terms=* Adult
* Aging
* Apoptosis
* Ataxia Telangiectasia Mutated Proteins
* Biomarkers
* Cellular Senescence
* Cumulus Cells
* DNA Breaks, Double-Stranded
* DNA Repair
* Embryo Transfer
* Female
* Fertilization in Vitro
* Histones
* Humans
* MRE11 Homologue Protein
* Prognosis
* RNA, Messenger
* Rad51 Recombinase
* Ubiquitin-Protein Ligases

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6147527
}}
{{medline-entry
|title=Cost effectiveness of population based [[BRCA1]] founder mutation testing in Sephardi Jewish women.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29288066
|abstract=Population-based [[BRCA1]]/BRCA2 founder-mutation testing has been demonstrated as cost effective compared with family history based testing in Ashkenazi Jewish women. However, only 1 of the 3 Ashkenazi Jewish [[BRCA1]]/BRCA2 founder mutations (185delAG[c.68_69delAG]), 5382insC[c.5266dupC]), and 6174delT[c.5946delT]) is found in the Sephardi Jewish population (185delAG[c.68_69delAG]), and the overall prevalence of BRCA mutations in the Sephardi Jewish population is accordingly lower (0.7% compared with 2.5% in the Ashkenazi Jewish population). Cost-effectiveness analyses of BRCA testing have not previously been performed at these lower BRCA prevalence levels seen in the Sephardi Jewish population. Here we present a cost-effectiveness analysis for UK and US populations comparing population testing with clinical criteria/family history-based testing in Sephardi Jewish women. A Markov model was built comparing the lifetime costs and effects of population-based [[BRCA1]] testing, with testing using family history-based clinical criteria in Sephardi Jewish women aged ≥30 years. [[BRCA1]] carriers identified were offered magnetic resonance imaging/mammograms and risk-reducing surgery. Costs are reported at 2015 prices. Outcomes include breast cancer, ovarian cancer, and excess deaths from heart disease. All costs and outcomes are discounted at 3.5%. The time horizon is lifetime, and perspective is payer. The incremental cost-effectiveness ratio per quality-adjusted life-year was calculated. Parameter uncertainty was evaluated through 1-way and probabilistic sensitivity analysis. Population testing resulted in gain in life expectancy of 12 months (quality-adjusted life-year = 1.00). The baseline discounted incremental cost-effectiveness ratio for UK population-based testing was £67.04/quality-adjusted life-year and for US population was $308.42/quality-adjusted life-year. Results were robust in the 1-way sensitivity analysis. The probabilistic sensitivity analysis showed 100% of simulations were cost effective at £20,000/quality-adjusted life-year UK and the $100,000/quality-adjusted life-year US willingness-to-pay thresholds. Scenario analysis showed that population testing remains cost effective in UK and US populations, even if premenopausal oophorectomy does not reduce breast cancer risk or if hormone replacement therapy compliance is nil. Population-based [[BRCA1]] testing is highly cost effective compared with clinical criteria-driven approach in Sephardi Jewish women. This supports changing the paradigm to population-based BRCA testing in the Jewish population, regardless of Ashkenazi/Sephardi ancestry.
|mesh-terms=* Adult
* Cost-Benefit Analysis
* Female
* Genes, BRCA1
* Genetic Testing
* Hereditary Breast and Ovarian Cancer Syndrome
* Heterozygote
* Hormone Replacement Therapy
* Humans
* Jews
* Life Expectancy
* Magnetic Resonance Imaging
* Mammography
* Markov Chains
* Middle Aged
* Mutation
* Ovariectomy
* Prophylactic Mastectomy
* Prophylactic Surgical Procedures
* Quality-Adjusted Life Years
* United Kingdom
* United States
|keywords=* BRCA
* Sephardi Jewish
* cost effectiveness
* population testing
|full-text-url=https://sci-hub.do/10.1016/j.ajog.2017.12.221
}}
{{medline-entry
|title=Replication Stress Shapes a Protective Chromatin Environment across Fragile Genomic Regions.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29249653
|abstract=Recent integrative epigenome analyses highlight the importance of functionally distinct chromatin states for accurate cell function. How these states are established and maintained is a matter of intense investigation. Here, we present evidence for DNA damage as an unexpected means to shape a protective chromatin environment at regions of recurrent replication stress (RS). Upon aberrant fork stalling, DNA damage signaling and concomitant [[H2AX]] phosphorylation coordinate the FACT-dependent deposition of macroH2A1.2, a histone variant that promotes DNA repair by homologous recombination ([[HR]]). MacroH2A1.2, in turn, facilitates the accumulation of the tumor suppressor and [[HR]] effector [[BRCA1]] at replication forks to protect from RS-induced DNA damage. Consequently, replicating primary cells steadily accrue macroH2A1.2 at fragile regions, whereas macroH2A1.2 loss in these cells triggers DNA damage signaling-dependent senescence, a hallmark of RS. Altogether, our findings demonstrate that recurrent DNA damage contributes to the chromatin landscape to ensure the epigenomic integrity of dividing cells.
|mesh-terms=* BRCA1 Protein
* Carcinogenesis
* Cell Division
* Cells, Cultured
* Cellular Senescence
* Chromatin
* DNA Damage
* DNA Repair
* DNA Replication
* Genomic Instability
* Histones
* Homologous Recombination
* Humans
* Signal Transduction
|keywords=* DNA repair
* FACT
* chromatin
* macro-histone
* macroH2A1.2
* replication stress
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5756112
}}
{{medline-entry
|title=Faulty [[BRCA1]], [[BRCA2]] genes: how poor is the prognosis?
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29017890
|abstract=We take a critical look at the meaning behind the number 87% given to 25-year-old Sophie, a [[BRCA1]] and [[BRCA2]] carrier. Sophie has been told she has an 87% chance of getting breast cancer. She is contemplating a preventive double mastectomy after genetic counseling and her physician's advice. Some 92% of British general practitioners are in favor of prophylactic mastectomy as a treatment option for women similar to Sophie. The treatment decision results, to a very large extent, from the size of the number (87%) alone. The central argument of this study is that physicians, their patients, and the public need a much better understanding on what is meant by probability estimates of 0.87. The figure on its own does not tell us much, and we need to be very cautious in its interpretation. It is important to know that the very same genetic and statistical models, and observed data, resulting in a verdict of an 87% lifetime chance of getting breast cancer, based on [[BRCA1]], [[BRCA2]], and familial information, simultaneously show Sophie to have a greater than 99% chance of surviving beyond the next 5 years cancer free. If she succeeds-the chances are overwhelmingly in her favor-then, given that fact, her chances of surviving a further 5 years are once again greater than 98%. Her chances of not dying due to breast cancer over the next 20 years are greater than 97%, a percentage that changes little if instead of 20 we write the number 30. In a word, although the diagnosis of a faulty BRAC gene may be a disappointment, there is no immediate peril and no need for undue alarm. Sophie, and her primary care providers, can carefully consider her options without feeling that they are under any kind of acute pressure. Whatever the threat, it is not an imminent one.
|mesh-terms=* BRCA1 Protein
* BRCA2 Protein
* Breast Neoplasms
* Decision Support Techniques
* Female
* Genes, BRCA1
* Genes, BRCA2
* Humans
* Life Expectancy
* Mastectomy
* Prognosis
|keywords=* BRCA1
* BRCA2
* Breast cancer
* Genetics
* Probability
* Risk
|full-text-url=https://sci-hub.do/10.1016/j.annepidem.2017.09.005
}}
{{medline-entry
|title=Ovarian Aging in Women With BRCA Germline Mutations.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28938488
|abstract=Recent clinical and laboratory studies suggested that women with BRCA mutations have lower ovarian reserve and their primordial follicle oocytes may be more prone to DNA damage; however, direct proof is lacking. To determine whether women with germline BRCA mutations have reduced primordial follicle reserve and increased oocyte DNA damage. A comparative laboratory study of ovarian tissue obtained from unaffected BRCA mutation carriers (BMCs) vs age-matched organ donor cadavers. Two academic centers. Of the 230 ovarian specimens from BMCs, 18 met the study inclusion criteria. Healthy ovaries from 12 organ donor cadavers served as controls. Histology and immunohistochemical analysis on paraffin-embedded ovarian sections. Primordial follicle density and the percentage of DNA double-strand break (DSB)-positive primordial follicle oocytes. Ovaries from BMCs had significantly lower primordial follicle densities than those of controls (11.2 ± 2.0 vs 44.2 ± 6.2 follicles/mm3; P = 0.0002). BRCA mutations were associated with increased DNA DSBs in primordial follicle oocytes (62% ± 5.2% vs 36% ± 3.4%; P = 0.0005). In subgroup analyses, both [[BRCA1]] and [[BRCA2]] mutations were associated with lower primordial follicle density (P = 0.0001 and 0.0030, respectively), and [[BRCA1]] mutations were associated with higher DNA DSBs (P = 0.0003) than controls. The rates of follicle decline (R2 = 0.74; P = 0.0001) and DNA DSB accumulation (R2 = 0.70; P = 0.0001) appeared to be accelerated, particularly in primordial follicle oocytes of BMCs over age 30 years. We provide direct evidence of diminished ovarian reserve as well as accelerated primordial follicle loss and oocyte DNA damage in women with BRCA mutations. These findings may further our understanding of ovarian aging, and be useful when counseling BMCs.
|mesh-terms=* Adult
* Aging
* BRCA1 Protein
* Biopsy
* Cadaver
* Case-Control Studies
* DNA Damage
* Female
* Genetic Carrier Screening
* Germ-Line Mutation
* Humans
* Oocytes
* Ovarian Follicle
* Ovarian Reserve
* Ovary
* Young Adult

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5630253
}}
{{medline-entry
|title=The expected benefit of preventive mastectomy on breast cancer incidence and mortality in BRCA mutation carriers, by age at mastectomy.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28914396
|abstract=Preventive breast surgery is offered to unaffected BRCA mutation carriers to prevent breast cancer incidence and mortality. The clinical benefit of preventive mastectomy can be measured in several ways, including extension of life expectancy (mean years of life gained) and by estimating the probability of surviving until age 80. We sought to estimate the expected benefit of a preventive mastectomy at various ages, using these indices of mortality, by simulating hypothetical cohorts of women. The age-specific annual risks of developing breast cancer were used to estimate the actuarial risk of developing breast cancer by age 80 for women with a [[BRCA1]] or [[BRCA2]] mutation. The probability of developing breast cancer before age 80 was then modified to include competing causes of death, including from ovarian cancer. The mortality rate from breast cancer after a diagnosis of breast cancer was set at 2% annually for the first 10 years and then 1% annually for years ten to twenty. The incidence rate and mortality rate from ovarian cancer were based on published literature. We assumed that preventive mastectomy was associated with complete protection against subsequent breast cancer. A series of simulations was conducted to evaluate the reduction in the probability of death (from all causes) until age 80, according to the age at mastectomy. The actuarial risk of developing breast cancer until age 80 was estimated to be 70.8%. The actual risk (incorporating competing risks) was 64.0%. The probability of being alive at age 80 by having a mastectomy at age 25 increased by 8.7% (from 42.7 to 51.3%). The estimated benefit declined with age at mastectomy; for surgery done at age 50 the improvement in survival to age 80 was much more modest (2.8% at age 80, from 42.7 to 45.5%). Among BRCA mutation carriers, the mortality benefit of preventive mastectomy at age 25 is substantial, but the expected benefit declines rapidly with increasing age at surgery.
|mesh-terms=* Adult
* Age Factors
* Aged
* Aged, 80 and over
* BRCA1 Protein
* BRCA2 Protein
* Breast Neoplasms
* Female
* Humans
* Life Expectancy
* Middle Aged
* Mutation
* Ovarian Neoplasms
* Ovariectomy
* Prophylactic Mastectomy
|keywords=* BRCA
* Breast cancer
* Mastectomy
* Ovarian cancer
|full-text-url=https://sci-hub.do/10.1007/s10549-017-4476-1
}}
{{medline-entry
|title=A [[BRCA1]]-Dependent DNA Damage Response in the Regenerating Adult Peripheral Nerve Milieu.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28585187
|abstract=It is not generally appreciated that DNA repair machinery has a critical role in the remodeling of neurons that adopt a regenerative phenotype. We identified that breast cancer 1 ([[BRCA1]])-dependent DNA activity, previously well known to repair cancer cells, is active in adult peripheral neurons and Schwann cells during their injury and regeneration response. Temporary or partial loss of [[BRCA1]] or blockade of its intraneuronal nuclear entry impaired outgrowth in neurons in vitro and impacted nerve regeneration and functional recovery in vivo. We found that distal axonal injury triggered a [[BRCA1]]-dependent DNA damage response (DDR) signal in neuronal soma. [[BRCA1]] also supported an enabling transcriptional program of injured neurons and supporting Schwann cells. Our findings indicate that [[BRCA1]] offers prominent functional roles in neurons and glial cells including key support for their physical and molecular integrity. Since [[BRCA1]] mutations are common in humans, this function of [[BRCA1]] in peripheral neurons and their glial partners warrants attention.
|mesh-terms=* Aging
* Animals
* BRCA1 Protein
* Cell Proliferation
* DNA Damage
* DNA Repair
* Models, Biological
* Nerve Crush
* Nerve Regeneration
* Neurites
* Oxidative Stress
* Peripheral Nerve Injuries
* Peripheral Nerves
* Rats, Sprague-Dawley
* Schwann Cells
* Sensory Receptor Cells
|keywords=* BRCA1
* DRG
* Neuron
* Peripheral nerve
* Regeneration
* Schwann cells
|full-text-url=https://sci-hub.do/10.1007/s12035-017-0574-7
}}
{{medline-entry
|title=The Histone Variant MacroH2A1 Is a [[BRCA1]] Ubiquitin Ligase Substrate.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28564596
|abstract=The breast- and ovarian-cancer-specific tumor suppressor [[BRCA1]] and its heterodimeric partner [[BARD1]] contain RING domains that implicate them as E3 ubiquitin ligases. Despite extensive efforts, the bona fide substrates of [[BRCA1]]/[[BARD1]] remain elusive. Here, we used recombinant GST fused to four UBA domains to enrich ubiquitinated proteins followed by a Lys-ε-Gly-Gly (diGly) antibody to enrich ubiquitinated tryptic peptides. This tandem affinity purification method coupled with mass spectrometry identified 101 putative [[BRCA1]]/[[BARD1]] E3 substrates. We identified the histone variant macroH2A1 from the screen and showed that [[BRCA1]]/[[BARD1]] ubiquitinates macroH2A1 at lysine 123 in vitro and in vivo. Primary human fibroblasts stably expressing a ubiquitination-deficient macroH2A1 mutant were defective in cellular senescence compared to their wild-type counterpart. Our study demonstrates that [[BRCA1]]/[[BARD1]] is a macroH2A1 E3 ligase and implicates a role for macroH2A1 K123 ubiquitination in cellular senescence.
|mesh-terms=* Amino Acid Sequence
* BRCA1 Protein
* Cell Line
* Cellular Senescence
* Chromatography, Affinity
* Histones
* Humans
* Lysine
* Substrate Specificity
* Ubiquitin
* Ubiquitin-Protein Ligases
* Ubiquitination
|keywords=* BRCA1
* E3 ligase substrate
* macroH2A1.1
* senescence
* ubiquitination
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6507409
}}
{{medline-entry
|title=A Multigene Test Could Cost-Effectively Help Extend Life Expectancy for Women at Risk of Hereditary Breast Cancer.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28407996
|abstract=The National Comprehensive Cancer Network recommends that women who carry gene variants that confer substantial risk for breast cancer consider risk-reduction strategies, that is, enhanced surveillance (breast magnetic resonance imaging and mammography) or prophylactic surgery. Pathogenic variants can be detected in women with a family history of breast or ovarian cancer syndromes by multigene panel testing. To investigate whether using a seven-gene test to identify women who should consider risk-reduction strategies could cost-effectively increase life expectancy. We estimated effectiveness and lifetime costs from a payer perspective for two strategies in two hypothetical cohorts of women (40-year-old and 50-year-old cohorts) who meet the National Comprehensive Cancer Network-defined family history criteria for multigene testing. The two strategies were the usual test strategy for variants in [[BRCA1]] and [[BRCA2]] and the seven-gene test strategy for variants in [[BRCA1]], [[BRCA2]], [[TP53]], [[PTEN]], [[CDH1]], [[STK11]], and [[PALB2]]. Women found to have a pathogenic variant were assumed to undergo either prophylactic surgery or enhanced surveillance. The incremental cost-effectiveness ratio for the seven-gene test strategy compared with the [[BRCA1]]/2 test strategy was $42,067 per life-year gained or $69,920 per quality-adjusted life-year gained for the 50-year-old cohort and $23,734 per life-year gained or $48,328 per quality-adjusted life-year gained for the 40-year-old cohort. In probabilistic sensitivity analysis, the seven-gene test strategy cost less than $100,000 per life-year gained in 95.7% of the trials for the 50-year-old cohort. Testing seven breast cancer-associated genes, followed by risk-reduction management, could cost-effectively improve life expectancy for women at risk of hereditary breast cancer.
|mesh-terms=* Adult
* Age Factors
* Aged
* Aged, 80 and over
* Biomarkers, Tumor
* Breast Neoplasms
* Cost-Benefit Analysis
* Decision Support Techniques
* Early Detection of Cancer
* Female
* Gene Expression Profiling
* Genetic Predisposition to Disease
* Genetic Testing
* Health Care Costs
* Heredity
* Humans
* Life Expectancy
* Magnetic Resonance Imaging
* Mammography
* Mastectomy
* Middle Aged
* Models, Economic
* Patient Selection
* Phenotype
* Predictive Value of Tests
* Prognosis
* Quality-Adjusted Life Years
* Risk Assessment
* Risk Factors
* Watchful Waiting
|keywords=* BRCA
* breast cancer
* cost-effectiveness
* multigene panel testing
|full-text-url=https://sci-hub.do/10.1016/j.jval.2017.01.006
}}
{{medline-entry
|title=Serum [[AMH]] levels in healthy women from [[BRCA1]]/2 mutated families: are they reduced?
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27907901
|abstract=Do [[BRCA1]]/2 mutation carriers have a compromised ovarian reserve compared to proven non-carriers, based on serum anti-Müllerian hormone ([[AMH]]) levels? [[BRCA1]]/2 mutation carriers do not show a lower serum [[AMH]] level in comparison to proven non-carriers, after adjustment for potential confounders. It has been suggested that the BRCA genes play a role in the process of ovarian reserve depletion, although previous studies have shown inconsistent results regarding the association between serum [[AMH]] levels and BRCA mutation status. Hence, it is yet unclear whether [[BRCA1]]/2 mutation carriers may indeed be at risk of a reduced reproductive lifespan. STUDY DESIGN, SIZE, DURATION: A multicenter, cross-sectional study was performed between January 2012 and February 2015 in 255 women. We needed to include 120 [[BRCA1]]/2 mutation carriers and 120 proven non-carriers to demonstrate a difference in [[AMH]] levels of 0.40 µg/l (SD ± 0.12 µg/l, two-sided alpha-error 0.05, power 80%). Healthy women aged 18-45 years who were referred to the Clinical Genetics Department and applied for predictive [[BRCA1]]/2 testing because of a familial [[BRCA1]]/2 mutation were asked to participate. A cross-sectional assessment was performed by measuring serum [[AMH]] levels and filling out a questionnaire. Multivariate linear regression analyses adjusted for age, current smoking and current hormonal contraceptive use were performed on log-transformed serum [[AMH]] levels. Out of 823 potentially eligible women, 421 (51.2%) were willing to participate, and of those, 166 (39%) did not meet our inclusion criteria. Two hundred and fifty-five women were available for analyses; 124 [[BRCA1]]/2 mutation carriers and 131 proven non-carriers. The median [range] [[AMH]] level in carriers was 1.90 µg/l [0.11-19.00] compared to 1.80 µg/l [0.11-10.00] in non-carriers (P = 0.34). Adjusted linear regression analysis revealed no reduction in [[AMH]] level in the carriers (relative change = 0.98 (95%CI, 0.77-1.22); P = 0.76). Participants were relatively young. Power was insufficient to analyze [[BRCA1]] and [[BRCA2]] mutation carriers separately. [[AMH]] levels may have been influenced by the use of hormonal contraceptives, though similar proportions of carriers and non-carriers were current users and adjustments were made to correct for potential confounding in our analysis. Limitations of the current analysis and limitations of the existing literature argue for prospective, well-controlled follow-up studies with recurrent [[AMH]] measurements to determine whether carriers might be at risk for low ovarian reserve and to definitively guide care. This study was partially financially supported by a personal grant for Inge A.P. Derks-Smeets, kindly provided by the Dutch Cancer Society (Grant Number UM 2011-5249). Theodora C. van Tilborg, Inge A.P. Derks-Smeets, Anna M.E. Bos, Jan C. Oosterwijk, Christine E. de Die-Smulders, Lizet E. van der Kolk, Wendy A.G. van Zelst-Stams, Maria E. Velthuizen, Marinus J.C. Eijkemans and Margreet G.E.M. Ausems have nothing to disclose. Ron J. van Golde has received unrestricted research grants from Ferring and Merck Serono, outside the submitted work. Annemieke Hoek received an unrestricted educational grant from Ferring pharmaceutical BV, The Netherlands and a speaker's fee for post graduate education from MSD pharmaceutical company, outside the submitted work. Joop S.E. Laven has received unrestricted research grants from Ferring, Merck Serono, Merck Sharpe