Редактирование: POLD1 (раздел)

==Publications==

{{medline-entry
|title=Epigenetic signatures of Werner syndrome occur early in life and are distinct from normal epigenetic aging processes.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31259468
|abstract=Werner Syndrome (WS) is an adult-onset segmental progeroid syndrome. Bisulfite pyrosequencing of repetitive DNA families revealed comparable blood DNA methylation levels between classical (18 [[WRN]]-mutant) or atypical WS (3 [[LMNA]]-mutant and 3 [[POLD1]]-mutant) patients and age- and sex-matched controls. WS was not associated with either age-related accelerated global losses of ALU, LINE1, and α-satellite DNA methylations or gains of rDNA methylation. Single CpG methylation was analyzed with Infinium MethylationEPIC arrays. In a correspondence analysis, atypical WS samples clustered together with the controls and were clearly separated from classical WS, consistent with distinct epigenetic pathologies. In classical WS, we identified 659 differentially methylated regions (DMRs) comprising 3,656 CpG sites and 613 RefSeq genes. The top DMR was located in the [[HOXA4]] promoter. Additional DMR genes included [[LMNA]], [[POLD1]], and 132 genes which have been reported to be differentially expressed in [[WRN]]-mutant/depleted cells. DMRs were enriched in genes with molecular functions linked to transcription factor activity and sequence-specific DNA binding to promoters transcribed by RNA polymerase II. We propose that transcriptional misregulation of downstream genes by the absence of [[WRN]] protein contributes to the variable premature aging phenotypes of WS. There were no CpG sites showing significant differences in DNA methylation changes with age between WS patients and controls. Genes with both WS- and age-related methylation changes exhibited a constant offset of methylation between [[WRN]]-mutant patients and controls across the entire analyzed age range. WS-specific epigenetic signatures occur early in life and do not simply reflect an acceleration of normal epigenetic aging processes.
|mesh-terms=* Aging
* Epigenesis, Genetic
* Humans
* Methylation
* Mutation
* Werner Syndrome
* Werner Syndrome Helicase
|keywords=* (classical and atypical) Werner syndrome
* bisulfite pyrosequencing
* methylation array
* premature aging
* segmental progeria
* transcription deficiency
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718529
}}
{{medline-entry
|title=[[POLD1]] deficiency is involved in cognitive function impairment in AD patients and SAMP8 mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30978525
|abstract=Age-related changes such as increased oxidative stress and DNA damage are important risk factors for Alzheimer's disease (AD). This study aimed to clarify the role of [[POLD1]], the catalytic subunit of DNA polymerase δ, in neurodegeneration symptoms of AD. [[POLD1]] expression levels were evaluated in patients with different neurodegenerative diseases by ELISA, RT-PCR and Western blot analysis. The impairment of cognitive ability in AD patients and senescence-accelerated mouse prone 8 (SAMP8) mice were evaluated by MMSE/MoCA score and Morris water maze (MWM) test. We found that serum concentration and expression levels of [[POLD1]] in lymphocytes were reduced in AD patients. The cognitive impairment in AD patients and SAMP8 mice was associated with reduced [[POLD1]] expression. In addition, [[POLD1]] knockdown led to premature senescence and increased DNA damage in primary neuronal cells of SAMP8 mice. In conclusion, this is the first study suggesting that the deficiency of [[POLD1]] may aggravate AD progression, and [[POLD1]] is a potential diagnostic marker and therapeutic target for AD.
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Alzheimer Disease
* Animals
* Cognition
* Cognition Disorders
* Cognitive Dysfunction
* DNA Polymerase III
* Disease Models, Animal
* Female
* Humans
* Lymphocytes
* Male
* Maze Learning
* Mice
* Middle Aged
* Oxidative Stress
|keywords=* Alzheimer’s disease
* DNA damage repair
* POLD1
* SAMP8
|full-text-url=https://sci-hub.do/10.1016/j.biopha.2019.108833
}}
{{medline-entry
|title=[[E2F1]] mediates the downregulation of [[POLD1]] in replicative senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30895337
|abstract=[[POLD1]], the catalytic subunit of DNA Pol δ, plays an important role in DNA synthesis and DNA damage repair, and [[POLD1]] is downregulated in replicative senescence and mediates cell aging. However, the mechanisms of age-related downregulation of [[POLD1]] expression have not been elucidated. In this study, four potential CpG islands in the [[POLD1]] promoter were found, and the methylation levels of the [[POLD1]] promoter were increased in aging 2BS cells, WI-38 cells and peripheral blood lymphocytes, especially at a single site, CpG 36, in CpG island 3. Then, the transcription factor [[E2F1]] was observed to bind to these sites. The binding affinity of [[E2F1]] for the [[POLD1]] promoter was found to show age-related attenuation and was confirmed to be positively regulated by the [[E2F1]] level and negatively regulated by [[POLD1]] promoter methylation. Moreover, cell senescence characteristics were observed in the cells transfected with shRNA-[[E2F1]] and could contribute to the downregulation of [[POLD1]] induced by the [[E2F1]] decline. Collectively, these results indicated that the attenuation of the binding affinity of [[E2F1]] for the [[POLD1]] promoter, mediated by an age-related decline in [[E2F1]] and increased methylation of CpG island 3, downregulates [[POLD1]] expression in aging.
|mesh-terms=* Adult
* Aged
* Aged, 80 and over
* Cells, Cultured
* Cellular Senescence
* CpG Islands
* DNA Methylation
* DNA Polymerase III
* DNA Repair
* DNA Replication
* Down-Regulation
* E2F1 Transcription Factor
* Female
* Gene Expression Regulation
* Healthy Volunteers
* Humans
* Male
* Middle Aged
* Promoter Regions, Genetic
* Young Adult
|keywords=* DNA methylation
* E2F1
* POLD1
* Replicative senescence
* Transcription factor
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588650
}}
{{medline-entry
|title=Mandibuloacral dysplasia: A premature ageing disease with aspects of physiological ageing.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29208544
|abstract=Mandibuloacral dysplasia (MAD) is a rare genetic condition characterized by bone abnormalities including localized osteolysis and generalized osteoporosis, skin pigmentation, lipodystrophic signs and mildly accelerated ageing. The molecular defects associated with MAD are mutations in [[LMNA]] or [[ZMPSTE24]] (FACE1) gene, causing type A or type B MAD, respectively. Downstream of [[LMNA]] or [[ZMPSTE24]] mutations, the lamin A precursor, prelamin A, is accumulated in cells and affects chromatin dynamics and stress response. A new form of mandibuloacral dysplasia has been recently associated with mutations in [[POLD1]] gene, encoding DNA polymerase delta, a major player in DNA replication. Of note, involvement of prelamin A in chromatin dynamics and recruitment of DNA repair factors has been also determined under physiological conditions, at the border between stress response and cellular senescence. Here, we review current knowledge on MAD clinical and pathogenetic aspects and highlight aspects typical of physiological ageing.
|mesh-terms=* Acro-Osteolysis
* Aging
* Aging, Premature
* Animals
* Humans
* Lamin Type A
* Lipodystrophy
* Mandible
* Membrane Proteins
* Metalloendopeptidases
* Mutation
|keywords=* Aging
* Lamin A/C gene (LMNA)
* Mandibuloacral dysplasia (MAD)
* Prelamin A
* Progeroid syndromes
* ZMPSTE24
|full-text-url=https://sci-hub.do/10.1016/j.arr.2017.12.001
}}
{{medline-entry
|title=[[POLD1]]: Central mediator of DNA replication and repair, and implication in cancer and other pathologies.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27320729
|abstract=The evolutionarily conserved human polymerase delta ([[POLD1]]) gene encodes the large p125 subunit which provides the essential catalytic activities of polymerase δ (Polδ), mediated by 5'-3' DNA polymerase and 3'-5' exonuclease moieties. [[POLD1]] associates with three smaller subunits (POLD2, [[POLD3]], POLD4), which together with Replication Factor C and Proliferating Nuclear Cell Antigen constitute the polymerase holoenzyme. Polδ function is essential for replication, with a primary role as the replicase for the lagging strand. Polδ also has an important proofreading ability conferred by the exonuclease activity, which is critical for ensuring replicative fidelity, but also serves to repair DNA lesions arising as a result of exposure to mutagens. Polδ has been shown to be important for multiple forms of DNA repair, including nucleotide excision repair, double strand break repair, base excision repair, and mismatch repair. A growing number of studies in the past decade have linked germline and sporadic mutations in [[POLD1]] and the other subunits of Polδ with human pathologies. Mutations in Polδ in mice and humans lead to genomic instability, mutator phenotype and tumorigenesis. The advent of genome sequencing techniques has identified damaging mutations in the proofreading domain of [[POLD1]] as the underlying cause of some inherited cancers, and suggested that mutations in [[POLD1]] may influence therapeutic management. In addition, mutations in [[POLD1]] have been identified in the developmental disorders of mandibular hypoplasia, deafness, progeroid features and lipodystrophy and atypical Werner syndrome, while changes in expression or activity of [[POLD1]] have been linked to senescence and aging. Intriguingly, some recent evidence suggests that [[POLD1]] function may also be altered in diabetes. We provide an overview of critical Polδ activities in the context of these pathologic conditions. 
|mesh-terms=* Aging
* Animals
* Carcinogenesis
* DNA Polymerase III
* DNA Repair
* DNA Replication
* Gene Expression Regulation
* Humans
* Mice
* Mutation
* Neoplasms
* Proliferating Cell Nuclear Antigen
* Protein Subunits
* Replication Protein C
* Signal Transduction
* Werner Syndrome
|keywords=* DNA damage response
* Hypermutation
* MDPL syndrome
* POLD1
* Polymerase delta
* Replication
* p125
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4969162
}}