A dual role of BRCA1 in two distinct homologous recombination mediated repair in response to replication arrest
Zhihui Feng,Junran Zhang +1 more
TLDR
The data established a molecular basis for the observation that defective BRCA1 leads to a high sensitivity to agents that cause replication blocks without being associated with DSBs, and implicate a novel mechanism by which loss of cell cycle checkpoints promotes B RCA1-associated tumorigenesis via enhancing HR defect resulting from BRC a1 deficiency.Abstract:
Homologous recombination (HR) is a major mechanism utilized to repair blockage of DNA replication forks. Here, we report that a sister chromatid exchange (SCE) generated by crossover-associated HR efficiently occurs in response to replication fork stalling before any measurable DNA double-strand breaks (DSBs). Interestingly, SCE produced by replication fork collapse following DNA DSBs creation is specifically suppressed by ATR, a central regulator of the replication checkpoint. BRCA1 depletion leads to decreased RPA2 phosphorylation (RPA2-P) following replication fork stalling but has no obvious effect on RPA2-P following replication fork collapse. Importantly, we found that BRCA1 promotes RAD51 recruitment and SCE induced by replication fork stalling independent of ATR. In contrast, BRCA1 depletion leads to a more profound defect in RAD51 recruitment and SCE induced by replication fork collapse when ATR is depleted. We concluded that BRCA1 plays a dual role in two distinct HR-mediated repair upon replication fork stalling and collapse. Our data established a molecular basis for the observation that defective BRCA1 leads to a high sensitivity to agents that cause replication blocks without being associated with DSBs, and also implicate a novel mechanism by which loss of cell cycle checkpoints promotes BRCA1-associated tumorigenesis via enhancing HR defect resulting from BRCA1 deficiency.read more
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Conflict of interest statement. None declared.
TL;DR: It is found that women over 50 are more likely to have a family history of diabetes, especially if they are obese, than women under the age of 50.
Journal ArticleDOI
Proteomic Profiling Identifies Dysregulated Pathways in Small Cell Lung Cancer and Novel Therapeutic Targets Including PARP1
Lauren Averett Byers,Jing Wang,Monique B. Nilsson,Junya Fujimoto,Pierre Saintigny,John S. Yordy,Uma Giri,Michael Peyton,You Hong Fan,Lixia Diao,Fatemeh Masrorpour,Li Shen,Wenbin Liu,Boris Duchemann,Praveen K. Tumula,Vikas Bhardwaj,James W. Welsh,Stephanie Weber,Bonnie S. Glisson,Neda Kalhor,Ignacio I. Wistuba,Luc Girard,Scott M. Lippman,Gordon B. Mills,Kevin R. Coombes,John N. Weinstein,John D. Minna,John V. Heymach +27 more
TL;DR: SCLC was significantly more sensitive to PARP inhibitors than were NSCLCs, and PARP inhibition downregulated key components of the DNA repair machinery and enhanced the efficacy of chemotherapy.
Journal ArticleDOI
GUARDIN is a p53-responsive long non-coding RNA that is essential for genomic stability.
Wang Lai Hu,Lei Jin,An Xu,Yufang Wang,Rick F. Thorne,Xudong Zhang,Xudong Zhang,Mian Wu,Mian Wu +8 more
TL;DR: It is demonstrated that the p53-responsive lncRNA GUARDIN is important for maintaining genomic integrity under steady-state conditions and after exposure to exogenous genotoxic stress and may constitute a target for cancer treatment.
Journal ArticleDOI
ATR/CHK1 inhibitors and cancer therapy.
TL;DR: The status of the development of ATR/CHK1 inhibitors is reviewed and the potential mechanisms by which ATR and CHK1 inhibition induces cell killing in the presence or absence of exogenous DNA damaging agents, such as RT and chemotherapeutic agents are discussed.
Journal ArticleDOI
Loss of BRCA1 or BRCA2 markedly increases the rate of base substitution mutagenesis and has distinct effects on genomic deletions
Judit Zámborszky,Bernadett Szikriszt,Judit Z. Gervai,Orsolya Pipek,Ádám Póti,Marcin Krzystanek,Dezső Ribli,János M. Szalai-Gindl,István Csabai,Zoltan Szallasi,Charles Swanton,Andrea L. Richardson,Dávid Szüts +12 more
TL;DR: The high rate of base substitution mutagenesis demonstrated by the experiments is likely to significantly contribute to the oncogenic effect of the inactivation of BRCA1 or BRCa2.
References
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Journal ArticleDOI
Cell-cycle checkpoints and cancer
Michael B. Kastan,Jiri Bartek +1 more
TL;DR: All life on earth must cope with constant exposure to DNA-damaging agents such as the Sun's radiation, and how cells respond to DNA damage are critical determinants of whether that individual will develop cancer.
Journal ArticleDOI
Association of BRCA1 with Rad51 in Mitotic and Meiotic Cells
Ralph Scully,Junjie Chen,Annemieke W. Plug,Yonghong Xiao,David R. Weaver,Jean Feunteun,Terry Ashley,David M. Livingston +7 more
TL;DR: Findings suggest a functional interaction between BRCA1 and Rad51 in the meiotic and mitotic cell cycles, which, in turn, suggests a role for BRC a1 in the control of recombination and of genome integrity.
Journal ArticleDOI
53BP1 Inhibits Homologous Recombination in Brca1-Deficient Cells by Blocking Resection of DNA Breaks
Samuel F. Bunting,Elsa Callen,Nancy Wong,Hua Tang Chen,Federica Polato,Amanda Gunn,Anne Bothmer,Niklas Feldhahn,Oscar Fernandez-Capetillo,Liu Cao,Xiaoling Xu,Chu-Xia Deng,Toren Finkel,Michel C. Nussenzweig,Michel C. Nussenzweig,Jeremy M. Stark,André Nussenzweig +16 more
TL;DR: It is shown that DNA breaks in Brca1-deficient cells are aberrantly joined into complex chromosome rearrangements by a process dependent on the nonhomologous end-joining (NHEJ) factors 53BP1 and DNA ligase 4, illustrating that HR and NHEJ compete to process DNA breaks that arise during DNA replication.
Conflict of interest statement. None declared.
TL;DR: It is found that women over 50 are more likely to have a family history of diabetes, especially if they are obese, than women under the age of 50.
Journal ArticleDOI
Human CtIP promotes DNA end resection
Alessandro A. Sartori,Claudia Lukas,Julia Coates,Martin Mistrik,Shuang Fu,Jiri Bartek,Richard Baer,Jiri Lukas,Stephen P. Jackson +8 more
TL;DR: These findings establish evolutionarily conserved roles for CtIP-like proteins in controlling DSB resection, checkpoint signalling and homologous recombination.