scholarly journals Rb family-independent activating E2F increases genome stability, promotes homologous recombination, and decreases non-homologous end joining

2020 ◽  
Vol 162 ◽  
pp. 103607
Author(s):  
Xun Pei ◽  
Elbert Du ◽  
Zhentao Sheng ◽  
Wei Du
Keyword(s):  
Homologous Recombination ◽  
Genome Stability ◽  
End Joining ◽  
Non Homologous End Joining

scholarly journals Loss of Cdc13 causes genome instability by a deficiency in replication-dependent telomere capping

2019 ◽  
Author(s):  
Rachel E Langston ◽  
Dominic Palazzola ◽  
Erin Bonnell ◽  
Raymund J. Wellinger ◽  
Ted Weinert
Keyword(s):  
Homologous Recombination ◽  
Genome Stability ◽  
Genome Instability ◽  
Chromosome Instability ◽  
S Phase ◽  
Temperature Sensitive ◽  
End Joining ◽  
Telomere Capping ◽  
Non Homologous End Joining

AbstractIn budding yeast, Cdc13, Stn1, and Ten1 form a telomere binding heterotrimer dubbed CST. Here we investigate the role of Cdc13/CST in maintaining genome stability, using a Chr VII disome system that can generate recombinants, loss, and enigmatic unstable chromosomes. In cells expressing a temperature sensitive CDC13 allele, cdc13F684S, unstable chromosomes frequently arise due to problems in or near a telomere. Hence, when Cdc13 is defective, passage through S phase causes Exo1-dependent ssDNA and unstable chromosomes, which then are the source for whole chromosome instability events (e.g. recombinants, chromosome truncations, dicentrics, and/or loss). Specifically, genome instability arises from a defect in Cdc13’s replication-dependent telomere capping function, not Cdc13s putative post-replication telomere capping function. Furthermore, the unstable chromosomes form without involvement of homologous recombination nor non-homologous end joining. Our data suggest that a Cdc13/CST defect in semi-conservative replication near the telomere leads to ssDNA and unstable chromosomes, which then are lost or subject to complex rearrangements. This system defines a links between replication-dependent chromosome capping and genome stability in the form of unstable chromosomes.

scholarly journals cGAS guards against chromosome end-to-end fusions during mitosis and facilitates replicative senescence

2021 ◽  
Author(s):  
Xiaocui Li ◽  
Xiaojuan Li ◽  
Chen Xie ◽  
Sihui Cai ◽  
Mengqiu Li ◽  
...  
Keyword(s):  
Genome Stability ◽  
Mitotic Chromosome ◽  
Replicative Senescence ◽  
Genome Instability ◽  
Strand Break ◽  
End Joining ◽  
Dsb Repair ◽  
End To End ◽  
Non Homologous End Joining ◽  
Sting Pathway

AbstractAs a sensor of cytosolic DNA, the role of cyclic GMP-AMP synthase (cGAS) in innate immune response is well established, yet how its functions in different biological conditions remain to be elucidated. Here, we identify cGAS as an essential regulator in inhibiting mitotic DNA double-strand break (DSB) repair and protecting short telomeres from end-to-end fusion independent of the canonical cGAS-STING pathway. cGAS associates with telomeric/subtelomeric DNA during mitosis when TRF1/TRF2/POT1 are deficient on telomeres. Depletion of cGAS leads to mitotic chromosome end-to-end fusions predominantly occurring between short telomeres. Mechanistically, cGAS interacts with CDK1 and positions them to chromosome ends. Thus, CDK1 inhibits mitotic non-homologous end joining (NHEJ) by blocking the recruitment of RNF8. cGAS-deficient human primary cells are defective in entering replicative senescence and display chromosome end-to-end fusions, genome instability and prolonged growth arrest. Altogether, cGAS safeguards genome stability by controlling mitotic DSB repair to inhibit mitotic chromosome end-to-end fusions, thus facilitating replicative senescence.

scholarly journals Proton Irradiation Increases the Necessity for Homologous Recombination Repair Along with the Indispensability of Non-Homologous End Joining

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 889 ◽  
Author(s):  
Klaudia Szymonowicz ◽  
Adam Krysztofiak ◽  
Jansje van der Linden ◽  
Ajvar Kern ◽  
Simon Deycmar ◽  
...  
Keyword(s):  
Dna Damage ◽  
Homologous Recombination ◽  
Proton Irradiation ◽  
Negative Impact ◽  
Particle Therapy ◽  
Homologous Recombination Repair ◽  
End Joining ◽  
X Ray ◽  
Recombination Repair ◽  
Non Homologous End Joining

Technical improvements in clinical radiotherapy for maximizing cytotoxicity to the tumor while limiting negative impact on co-irradiated healthy tissues include the increasing use of particle therapy (e.g., proton therapy) worldwide. Yet potential differences in the biology of DNA damage induction and repair between irradiation with X-ray photons and protons remain elusive. We compared the differences in DNA double strand break (DSB) repair and survival of cells compromised in non-homologous end joining (NHEJ), homologous recombination repair (HRR) or both, after irradiation with an equal dose of X-ray photons, entrance plateau (EP) protons, and mid spread-out Bragg peak (SOBP) protons. We used super-resolution microscopy to investigate potential differences in spatial distribution of DNA damage foci upon irradiation. While DNA damage foci were equally distributed throughout the nucleus after X-ray photon irradiation, we observed more clustered DNA damage foci upon proton irradiation. Furthermore, deficiency in essential NHEJ proteins delayed DNA repair kinetics and sensitized cells to both, X-ray photon and proton irradiation, whereas deficiency in HRR proteins sensitized cells only to proton irradiation. We assume that NHEJ is indispensable for processing DNA DSB independent of the irradiation source, whereas the importance of HRR rises with increasing energy of applied irradiation.

scholarly journals A role for the p53 tumour suppressor in regulating the balance between homologous recombination and non-homologous end joining

Open Biology ◽  
2016 ◽  
Vol 6 (9) ◽  
pp. 160225 ◽  
Author(s):  
Sylvie Moureau ◽  
Janna Luessing ◽  
Emma Christina Harte ◽  
Muriel Voisin ◽  
Noel Francis Lowndes
Keyword(s):  
Dna Damage ◽  
Homologous Recombination ◽  
Tumour Suppressor ◽  
Cycle Phase ◽  
Repair Pathway ◽  
End Joining ◽  
Dsb Repair ◽  
Pathway Choice ◽  
Non Homologous End Joining ◽  
End Resection

Loss of p53, a transcription factor activated by cellular stress, is a frequent event in cancer. The role of p53 in tumour suppression is largely attributed to cell fate decisions. Here, we provide evidence supporting a novel role for p53 in the regulation of DNA double-strand break (DSB) repair pathway choice. 53BP1, another tumour suppressor, was initially identified as p53 Binding Protein 1, and has been shown to inhibit DNA end resection, thereby stimulating non-homologous end joining (NHEJ). Yet another tumour suppressor, BRCA1, reciprocally promotes end resection and homologous recombination (HR). Here, we show that in both human and mouse cells, the absence of p53 results in impaired 53BP1 focal recruitment to sites of DNA damage induced by ionizing radiation. This effect is largely independent of cell cycle phase and the extent of DNA damage. In p53-deficient cells, diminished localization of 53BP1 is accompanied by a reciprocal increase in BRCA1 recruitment to DSBs. Consistent with these findings, we demonstrate that DSB repair via NHEJ is abrogated, while repair via homology-directed repair (HDR) is stimulated. Overall, we propose that in addition to its role as an ‘effector’ protein in the DNA damage response, p53 plays a role in the regulation of DSB repair pathway choice.

Anti-silencing factor 1A is associated with genome stability maintenance of mouse preimplantation embryos†

2020 ◽  
Vol 102 (4) ◽  
pp. 817-827
Author(s):  
Kai Deng ◽  
Wanyou Feng ◽  
Xiaohua Liu ◽  
Xiaoping Su ◽  
Erwei Zuo ◽  
...  
Keyword(s):  
Embryonic Development ◽  
Genome Stability ◽  
Mouse Embryos ◽  
Preimplantation Embryos ◽  
End Joining ◽  
Dna Damages ◽  
Developmental Potential ◽  
Damage Repair ◽  
Non Homologous End Joining ◽  
Early Mouse

Abstract Genome stability is critical for the normal development of preimplantation embryos, as DNA damages may result in mutation and even embryo lethality. Anti-silencing factor 1A (ASF1A) is a histone chaperone and enriched in the MII oocytes as a maternal factor, which may be associated with the maintenance of genome stability. Thus, this study was undertaken to explore the role of ASF1A in maintaining the genome stability of early mouse embryos. The ASF1A expressed in the preimplantation embryos and displayed a dynamic pattern throughout the early embryonic development. Inhibition of ASF1A expression decreased embryonic development and increased DNA damages. Overexpression of ASF1A improved the developmental potential and decreased DNA damages. When 293T cells that had been integrated with RGS-NHEJ were co-transfected with plasmids of pcDNA3.1-ASF1A, gRNA-NHEJ, and hCas9, less cells expressed eGFP, indicating that non-homologous end joining was reduced by ASF1A. When 293T cells were co-transfected with plasmids of HR-donor, gRNA-HR, hCas9, and pcDNA3.1-ASF1A, more cells expressed eGFP, indicating that homologous recombination (HR) was enhanced by ASF1A. These results indicate that ASF1A may be associated with the genome stability maintenance of early mouse embryos and this action may be mediated by promoting DNA damage repair through HR pathway.

Homologous recombination and non-homologous end-joining repair pathways in bovine embryos with different developmental competence

2012 ◽  
Vol 318 (16) ◽  
pp. 2049-2058 ◽  
Author(s):  
Marcos Henrique Barreta ◽  
Bernardo Garziera Gasperin ◽  
Vitor Braga Rissi ◽  
Matheus Pedrotti de Cesaro ◽  
Rogério Ferreira ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Developmental Competence ◽  
Bovine Embryos ◽  
End Joining ◽  
Repair Pathways ◽  
Non Homologous End Joining
Sign in / Sign up

Export Citation Format

Share Document