The MRE11–RAD50–NBS1 Complex Conducts the Orchestration of Damage Signaling and Outcomes to Stress in DNA Replication and Repair

Annual Review of Biochemistry, Год журнала: 2018, Номер 87(1), С. 263 - 294

Опубликована: Май 1, 2018

Genomic instability in disease and its fidelity health depend on the DNA damage response (DDR), regulated part from complex of meiotic recombination 11 homolog 1 (MRE11), ATP-binding cassette-ATPase (RAD50), phosphopeptide-binding Nijmegen breakage syndrome protein (NBS1). The MRE11-RAD50-NBS1 (MRN) forms a multifunctional DDR machine. Within network assemblies, MRN is core conductor for initial sustained responses to double-strand breaks, stalled replication forks, dysfunctional telomeres, viral infection. can interfere with cancer therapy an attractive target precision medicine. Its conformations change paradigm whereby kinases initiate sensing. Delineated results reveal kinase activation, posttranslational targeting, functional scaffolding, storing binding energy enabling access, interactions hub proteins such as A (RPA), distinct networks at breaks forks. biochemistry provides prototypic insights into how it initiates, implements, regulates genomic stress.

Язык: Английский

---

How cells ensure correct repair of DNA double-strand breaks

Journal of Biological Chemistry, Год журнала: 2018, Номер 293(27), С. 10502 - 10511

Опубликована: Фев. 8, 2018

DNA double-strand breaks (DSBs) arise regularly in cells and when left unrepaired cause senescence or cell death. Homologous recombination (HR) nonhomologous end-joining (NHEJ) are the two major DNA-repair pathways. Whereas HR allows faithful DSB repair healthy growth, NHEJ has higher potential to contribute mutations malignancy. Many regulatory mechanisms influence which of these pathways is used repair. These depend on cycle, post-translational modifications, chromatin effects. Here, we summarize current research into mechanisms, with a focus mammalian cells, also discuss by "alternative end-joining" single-strand annealing.

Язык: Английский

---

NAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome

Nature Communications, Год журнала: 2019, Номер 10(1)

Опубликована: Ноя. 21, 2019

Abstract Metabolic dysfunction is a primary feature of Werner syndrome (WS), human premature aging disease caused by mutations in the gene encoding (WRN) DNA helicase. WS patients exhibit severe metabolic phenotypes, but underlying mechanisms are not understood, and whether deficit can be targeted for therapeutic intervention has been determined. Here we report impaired mitophagy depletion NAD + , fundamental ubiquitous molecule, patient samples invertebrate models. WRN regulates transcription key biosynthetic enzyme nicotinamide nucleotide adenylyltransferase 1 (NMNAT1). repletion restores profiles improves mitochondrial quality through DCT-1 ULK-1-dependent mitophagy. At organismal level, remarkably extends lifespan delays accelerated aging, including stem cell dysfunction, Caenorhabditis elegans Drosophila melanogaster models WS. Our findings suggest that mediated function mitophagy, bolstering cellular levels counteracts phenotypes.

Язык: Английский

---

Repair of DNA Double-Strand Breaks by the Nonhomologous End Joining Pathway

Annual Review of Biochemistry, Год журнала: 2021, Номер 90(1), С. 137 - 164

Опубликована: Фев. 9, 2021

DNA double-strand breaks pose a serious threat to genome stability. In vertebrates, these are predominantly repaired by nonhomologous end joining (NHEJ), which pairs ends in multiprotein synaptic complex promote their direct ligation. NHEJ is highly versatile pathway that uses an array of processing enzymes modify damaged and enable The mechanisms synapsis have important implications for Rapid stable necessary limit chromosome translocations result from the mispairing ends. Furthermore, must be tightly regulated minimize mutations at break site. Here, we review our current mechanistic understanding vertebrate NHEJ, with particular focus on processing.

Язык: Английский

---

SARS-CoV-2 infection induces DNA damage, through CHK1 degradation and impaired 53BP1 recruitment, and cellular senescence

Nature Cell Biology, Год журнала: 2023, Номер 25(4), С. 550 - 564

Опубликована: Март 9, 2023

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the RNA virus responsible for disease 2019 (COVID-19) pandemic. Although SARS-CoV-2 was reported to alter several cellular pathways, its impact on DNA integrity and mechanisms involved remain unknown. Here we show that causes damage elicits an altered response. Mechanistically, proteins ORF6 NSP13 cause degradation of response kinase CHK1 through proteasome autophagy, respectively. loss leads deoxynucleoside triphosphate (dNTP) shortage, causing impaired S-phase progression, damage, pro-inflammatory pathways activation senescence. Supplementation deoxynucleosides reduces that. Furthermore, N-protein impairs 53BP1 focal recruitment by interfering with damage-induced long non-coding RNAs, thus reducing repair. Key observations are recapitulated in SARS-CoV-2-infected mice patients COVID-19. We propose SARS-CoV-2, boosting ribonucleoside levels promote replication at expense dNTPs hijacking RNAs' biology, threatens genome activation, induction inflammation

Язык: Английский

---

Cell cycle-dependent phosphorylation regulates RECQL4 pathway choice and ubiquitination in DNA double-strand break repair

Nature Communications, Год журнала: 2017, Номер 8(1)

Опубликована: Дек. 5, 2017

Abstract Pathway choice within DNA double-strand break (DSB) repair is a tightly regulated process to maintain genome integrity. RECQL4, deficient in Rothmund-Thomson Syndrome, promotes the two major DSB pathways, non-homologous end joining (NHEJ) and homologous recombination (HR). Here we report that RECQL4 coordinates NHEJ HR different cell cycle phases. interacts with Ku70 promote G1 when overall cyclin-dependent kinase (CDK) activity low. During S/G2 phases, CDK1 CDK2 (CDK1/2) phosphorylate on serines 89 251, enhancing MRE11/RECQL4 interaction recruitment DSBs. After phosphorylation, ubiquitinated by DDB1-CUL4A E3 ubiquitin ligase, which facilitates its accumulation at Phosphorylation of stimulates helicase activity, resection, increases survival after ionizing radiation, prevents cellular senescence. Collectively, propose modulates pathway cycle-dependent manner.

Язык: Английский

---

Nonhomologous end joining: new accessory factors fine tune the machinery

Trends in Genetics, Год журнала: 2021, Номер 37(6), С. 582 - 599

Опубликована: Март 27, 2021

Язык: Английский

---

Recent Advances in Understanding Werner Syndrome

F1000Research, Год журнала: 2017, Номер 6, С. 1779 - 1779

Опубликована: Сен. 28, 2017

Aging, the universal phenomenon, affects human health and is primary risk factor for major disease pathologies. Progeroid diseases, which mimic aging at an accelerated rate, have provided cues in understanding hallmarks of aging. Mutations DNA repair genes as well telomerase subunits are known to cause progeroid syndromes. Werner syndrome (WS), characterized by aging, autosomal-recessive genetic disorder. Hallmarks that define process include genomic instability, telomere attrition, epigenetic alterations, loss proteostasis, deregulation nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication. WS recapitulates these shows increased incidence early onset specific cancers. Genome integrity stability ensure normal functioning mainly guarded machinery telomeres. WRN, being a RecQ helicase, protects genome regulating pathways Recent advances research elucidated WRN's role pathway choice regulation, maintenance, resolution complex structures, maintenance.

Язык: Английский

---

Plugged into the Ku-DNA hub: The NHEJ network

Progress in Biophysics and Molecular Biology, Год журнала: 2019, Номер 147, С. 62 - 76

Опубликована: Март 6, 2019

Язык: Английский

---

Roles of RNase P and Its Subunits

Trends in Genetics, Год журнала: 2017, Номер 33(9), С. 594 - 603

Опубликована: Июль 8, 2017

Язык: Английский

---