scholarly journals Deficiency in Bre1 Impairs Homologous Recombination Repair and Cell Cycle Checkpoint Response to Radiation Damage in Mammalian Cells

2010 ◽  
Vol 174 (5) ◽  
pp. 558-565 ◽  
Author(s):  
Sophia B. Chernikova ◽  
Jennifer A. Dorth ◽  
Olga V. Razorenova ◽  
John C. Game ◽  
J. Martin Brown
Keyword(s):  
Cell Cycle ◽  
Homologous Recombination ◽  
Radiation Damage ◽  
Mammalian Cells ◽  
Cell Cycle Checkpoint ◽  
Homologous Recombination Repair ◽  
Checkpoint Response ◽  
Recombination Repair ◽  
Cycle Checkpoint

The cell-cycle checkpoint kinase Chk1 is required for mammalian homologous recombination repair

2005 ◽  
Vol 7 (2) ◽  
pp. 195-201 ◽  
Author(s):  
Claus Storgaard Sørensen ◽  
Lasse Tengbjerg Hansen ◽  
Jaroslaw Dziegielewski ◽  
Randi G. Syljuåsen ◽  
Cecilia Lundin ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Homologous Recombination ◽  
Cell Cycle Checkpoint ◽  
Homologous Recombination Repair ◽  
Checkpoint Kinase ◽  
Recombination Repair ◽  
Cycle Checkpoint

scholarly journals Inhibition of the ATR kinase enhances 5-FU sensitivity independently of nonhomologous end-joining and homologous recombination repair pathways

2020 ◽  
Vol 295 (37) ◽  
pp. 12946-12961
Author(s):  
Soichiro S. Ito ◽  
Yosuke Nakagawa ◽  
Masaya Matsubayashi ◽  
Yoshihiko M. Sakaguchi ◽  
Shinko Kobashigawa ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Mammalian Cells ◽  
Cell Cycle Checkpoint ◽  
Nonhomologous End Joining ◽  
Homologous Recombination Repair ◽  
Dna Breaks ◽  
End Joining ◽  
Nucleotide Synthesis ◽  
Recombination Repair ◽  
Repair Pathways

The anticancer agent 5-fluorouracil (5-FU) is cytotoxic and often used to treat various cancers. 5-FU is thought to inhibit the enzyme thymidylate synthase, which plays a role in nucleotide synthesis and has been found to induce single- and double-strand DNA breaks. ATR Ser/Thr kinase (ATR) is a principal kinase in the DNA damage response and is activated in response to UV– and chemotherapeutic drug–induced DNA replication stress, but its role in cellular responses to 5-FU is unclear. In this study, we examined the effect of ATR inhibition on 5-FU sensitivity of mammalian cells. Using immunoblotting, we found that 5-FU treatment dose-dependently induced the phosphorylation of ATR at the autophosphorylation site Thr-1989 and thereby activated its kinase. Administration of 5-FU with a specific ATR inhibitor remarkably decreased cell survival, compared with 5-FU treatment combined with other major DNA repair kinase inhibitors. Of note, the ATR inhibition enhanced induction of DNA double-strand breaks and apoptosis in 5-FU–treated cells. Using gene expression analysis, we found that 5-FU induced the activation of the intra-S cell-cycle checkpoint. Cells lacking BRCA2 were sensitive to 5-FU in the presence of ATR inhibitor. Moreover, ATR inhibition enhanced the efficacy of the 5-FU treatment, independently of the nonhomologous end-joining and homologous recombination repair pathways. These findings suggest that ATR could be a potential therapeutic target in 5-FU–based chemotherapy.

scholarly journals Undamaged DNA Transmits and Enhances DNA Damage Checkpoint Signals in Early Embryos

2007 ◽  
Vol 27 (19) ◽  
pp. 6852-6862 ◽  
Author(s):  
Aimin Peng ◽  
Andrea L. Lewellyn ◽  
James L. Maller
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Nuclear Dna ◽  
Cell Cycle Checkpoint ◽  
Dna Damage Checkpoint ◽  
Checkpoint Signaling ◽  
Checkpoint Response ◽  
Egg Extracts ◽  
Cycle Checkpoint ◽  
Damaged Dna

ABSTRACT In Xenopus laevis embryos, the midblastula transition (MBT) at the 12th cell division marks initiation of critical developmental events, including zygotic transcription and the abrupt inclusion of gap phases into the cell cycle. Interestingly, although an ionizing radiation-induced checkpoint response is absent in pre-MBT embryos, introduction of a threshold amount of undamaged plasmid or sperm DNA allows a DNA damage checkpoint response to be activated. We show here that undamaged threshold DNA directly participates in checkpoint signaling, as judged by several dynamic changes, including H2AX phosphorylation, ATM phosphorylation and loading onto chromatin, and Chk1/Chk2 phosphorylation and release from nuclear DNA. These responses on physically separate threshold DNA require γ-H2AX and are triggered by an ATM-dependent soluble signal initiated by damaged DNA. The signal persists in egg extracts even after damaged DNA is removed from the system, indicating that the absence of damaged DNA is not sufficient to end the checkpoint response. The results identify a novel mechanism by which undamaged DNA enhances checkpoint signaling and provide an example of how the transition to cell cycle checkpoint activation during development is accomplished by maternally programmed increases in the DNA-to-cytoplasm ratio.

scholarly journals PARP inhibition during alkylation-induced genotoxic stress signals a cell cycle checkpoint response mediated by ATM

DNA Repair ◽  
2009 ◽  
Vol 8 (11) ◽  
pp. 1264-1272 ◽  
Author(s):  
Michael J. Carrozza ◽  
Donna F. Stefanick ◽  
Julie K. Horton ◽  
Padmini S. Kedar ◽  
Samuel H. Wilson
Keyword(s):  
Cell Cycle ◽  
Genotoxic Stress ◽  
Cell Cycle Checkpoint ◽  
Parp Inhibition ◽  
Checkpoint Response ◽  
Cycle Checkpoint ◽  
A Cell ◽  
Stress Signals

scholarly journals Methylator-induced, Mismatch Repair-dependent G2 Arrest Is Activated through Chk1 and Chk2

2005 ◽  
Vol 16 (3) ◽  
pp. 1513-1526 ◽  
Author(s):  
Aaron W. Adamson ◽  
Dillon I. Beardsley ◽  
Wan-Ju Kim ◽  
Yajuan Gao ◽  
R. Baskaran ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Mismatch Repair ◽  
Cell Cycle Checkpoint ◽  
Exact Nature ◽  
Dependent Manner ◽  
Molecular Scaffold ◽  
Checkpoint Response ◽  
Nuclear Exclusion ◽  
Cycle Checkpoint ◽  
Methylating Agents

SN1 DNA methylating agents such as the nitrosourea N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) elicit a G2/M checkpoint response via a mismatch repair (MMR) system-dependent mechanism; however, the exact nature of the mechanism governing MNNG-induced G2/M arrest and how MMR mechanistically participates in this process are unknown. Here, we show that MNNG exposure results in activation of the cell cycle checkpoint kinases ATM, Chk1, and Chk2, each of which has been implicated in the triggering of the G2/M checkpoint response. We document that MNNG induces a robust, dose-dependent G2 arrest in MMR and ATM-proficient cells, whereas this response is abrogated in MMR-deficient cells and attenuated in ATM-deficient cells treated with moderate doses of MNNG. Pharmacological and RNA interference approaches indicated that Chk1 and Chk2 are both required components for normal MNNG-induced G2 arrest. MNNG-induced nuclear exclusion of the cell cycle regulatory phosphatase Cdc25C occurred in an MMR-dependent manner and was compromised in cells lacking ATM. Finally, both Chk1 and Chk2 interact with the MMR protein MSH2, and this interaction is enhanced after MNNG exposure, supporting the notion that the MMR system functions as a molecular scaffold at the sites of DNA damage that facilitates activation of these kinases.

Research progress of PARP inhibitor monotherapy and combination therapy for endometrial cancer.

2021 ◽  
Vol 22 ◽  
Author(s):  
Ke Shen ◽  
Li Yang ◽  
Fei-Yan Li ◽  
Feng Zhang ◽  
Lei-Lei Ding ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Homologous Recombination ◽  
Tumor Cells ◽  
Checkpoint Inhibitors ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Cell Cycle Checkpoint ◽  
Research Progress ◽  
Homologous Recombination Repair ◽  
Recombination Repair

: Endometrial cancer is one of the three most common malignant tumors in the female reproductive system. Advanced and recurrent endometrial cancers have poor prognoses and lack effective treatments. Poly(ADP-ribose) polymerase (PARP) inhibitors have been applied to many different types of tumors, and they can selectively kill tumor cells that are defective in homologous recombination repair. Endometrial cancer is characterized by mutations in homologous recombination repair genes; accordingly, PARP inhibitors have achieved positive results in off-label treatments of endometrial cancer cases. Clinical trials of PARP inhibitors as monotherapies and within combination therapies for endometrial cancer are ongoing. For this review, we searched PubMed with "endometrial cancer" and "PARP inhibitor" as keywords, and we used "olaparib", "rucaparib", "niraparib" and "talazoparib" as search terms in clinicaltrials.gov for ongoing trials. The literature search ended in October 2020, and only English-language publications were selected. Multiple studies confirm that PARP inhibitors play an important role in killing tumor cells with defects in homologous recombination repair. Its combination with immune checkpoint inhibitors, PI3K/AKT/mTOR pathway inhibitors, cell cycle checkpoint inhibitors, and other drugs can improve the treatment of endometrial cancer.

scholarly journals Dissociation of p53-mediated suppression of homologous recombination from G1/S cell cycle checkpoint control

Oncogene ◽  
2000 ◽  
Vol 19 (5) ◽  
pp. 632-639 ◽  
Author(s):  
Henning Willers ◽  
Ellen E McCarthy ◽  
Biao Wu ◽  
Hannah Wunsch ◽  
Wei Tang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Homologous Recombination ◽  
Cell Cycle Checkpoint ◽  
Checkpoint Control ◽  
Cycle Checkpoint

scholarly journals Esc2 and Sgs1 Act in Functionally Distinct Branches of the Homologous Recombination Repair Pathway inSaccharomyces cerevisiae

2009 ◽  
Vol 20 (6) ◽  
pp. 1683-1694 ◽  
Author(s):  
Hocine W. Mankouri ◽  
Hien-Ping Ngo ◽  
Ian D. Hickson
Keyword(s):  
Dna Damage ◽  
Homologous Recombination ◽  
Structural Similarity ◽  
S Phase ◽  
Homologous Recombination Repair ◽  
Dna Damage Checkpoint ◽  
Checkpoint Signaling ◽  
Checkpoint Response ◽  
Recombination Repair ◽  
Anemia Group

Esc2 is a member of the RENi family of SUMO-like domain proteins and is implicated in gene silencing in Saccharomyces cerevisiae. Here, we identify a dual role for Esc2 during S-phase in mediating both intra-S-phase DNA damage checkpoint signaling and preventing the accumulation of Rad51-dependent homologous recombination repair (HRR) intermediates. These roles are qualitatively similar to those of Sgs1, the yeast ortholog of the human Bloom's syndrome protein, BLM. However, whereas mutation of either ESC2 or SGS1 leads to the accumulation of unprocessed HRR intermediates in the presence of MMS, the accumulation of these structures in esc2 (but not sgs1) mutants is entirely dependent on Mph1, a protein that shows structural similarity to the Fanconi anemia group M protein (FANCM). In the absence of both Esc2 and Sgs1, the intra-S-phase DNA damage checkpoint response is compromised after exposure to MMS, and sgs1esc2 cells attempt to undergo mitosis with unprocessed HRR intermediates. We propose a model whereby Esc2 acts in an Mph1-dependent process, separately from Sgs1, to influence the repair/tolerance of MMS-induced lesions during S-phase.

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