Редактирование: DNA2 (раздел)

==Publications==

{{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=Replication Stress at Telomeric and Mitochondrial DNA: Common Origins and Consequences on Ageing.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31597307
|abstract=Senescence is defined as a stress-induced durable cell cycle arrest. We herein revisit the origin of two of these stresses, namely mitochondrial metabolic compromise, associated with reactive oxygen species (ROS) production, and replicative senescence, activated by extreme telomere shortening. We discuss how replication stress-induced DNA damage of telomeric DNA (telDNA) and mitochondrial DNA (mtDNA) can be considered a common origin of senescence in vitro, with consequences on ageing in vivo. Unexpectedly, mtDNA and telDNA share common features indicative of a high degree of replicative stress, such as G-quadruplexes, D-loops, RNA:DNA heteroduplexes, epigenetic marks, or supercoiling. To avoid these stresses, both compartments use similar enzymatic strategies involving, for instance, endonucleases, topoisomerases, helicases, or primases. Surprisingly, many of these replication helpers are active at both telDNA and mtDNA (e.g., RNAse H1, [[FEN1]], [[DNA2]], RecQ helicases, Top2α, Top2β, [[TOP3A]], DNMT1/3a/3b, SIRT1). In addition, specialized telomeric proteins, such as [[TERT]] (telomerase reverse transcriptase) and TERC (telomerase RNA component), or TIN2 (shelterin complex), shuttle from telomeres to mitochondria, and, by doing so, modulate mitochondrial metabolism and the production of ROS, in a feedback manner. Hence, mitochondria and telomeres use common weapons and cooperate to resist/prevent replication stresses, otherwise producing common consequences, namely senescence and ageing.
|mesh-terms=* Aging
* Animals
* Cellular Senescence
* DNA Damage
* DNA Replication
* DNA, Mitochondrial
* Epigenesis, Genetic
* Humans
* Mitochondria
* Oxidative Stress
* Stress, Physiological
* Telomere
* Telomere Homeostasis
* Telomere Shortening
|keywords=* G-quadruplex
* R-loop
* ageing
* helicase
* mitochondria
* replication stress
* senescence
* telomere
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801922
}}
{{medline-entry
|title=Mutations in DNA replication genes reduce yeast life span.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/12024027
|abstract=Surprisingly, the contribution of defects in DNA replication to the determination of yeast life span has never been directly investigated. We show that a replicative yeast helicase/nuclease, encoded by [[DNA2]] and a member of the same helicase subfamily as the RecQ helicases, is required for normal life span. All of the phenotypes of old wild-type cells, for example, extended cell cycle time, age-related transcriptional silencing defects, and nucleolar reorganization, occur after fewer generations in dna2 mutants than in the wild type. In addition, the life span of dna2 mutants is extended by expression of an additional copy of SIR2 or by deletion of FOB1, which also increase wild-type life span. The ribosomal DNA locus and the nucleolus seem to be particularly sensitive to defects in dna2 mutants, although in dna2 mutants extrachromosomal ribosomal circles do not accumulate during the aging of a mother cell. Several other replication mutations, such as rad27 Delta, encoding the FEN-1 nuclease involved in several aspects of genomic stability, also show premature aging. We propose that replication fork failure due to spontaneous, endogenous DNA damage and attendant genomic instability may contribute to replicative senescence. This may imply that the genomic instability, segmental premature aging symptoms, and cancer predisposition associated with the human RecQ helicase diseases, such as Werner, Bloom, and Rothmund-Thomson syndromes, are also related to replicative stress.
|mesh-terms=* Adenosine Triphosphatases
* Aging
* DNA Helicases
* DNA Replication
* DNA-Binding Proteins
* Endodeoxyribonucleases
* Flap Endonucleases
* Fungal Proteins
* Histone Deacetylases
* Mutation
* Saccharomyces cerevisiae Proteins
* Silent Information Regulator Proteins, Saccharomyces cerevisiae
* Sirtuin 1
* Sirtuin 2
* Sirtuins
* Trans-Activators
* Yeasts

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC133874
}}