The mismatch repair system is required for S-phase checkpoint activation

  title={The mismatch repair system is required for S-phase checkpoint activation},
  author={Kevin D. Brown and Abhilasha V. Rathi and Ravindra Kamath and Dillon I Beardsley and Qimin Zhan and Jennifer L. Mannino and R Baskaran},
  journal={Nature Genetics},
Defective S-phase checkpoint activation results in an inability to downregulate DNA replication following genotoxic insult such as exposure to ionizing radiation. This 'radioresistant DNA synthesis' (RDS) is a phenotypic hallmark of ataxia–telangiectasia, a cancer-prone disorder caused by mutations in ATM. The mismatch repair system principally corrects nucleotide mismatches that arise during replication. Here we show that the mismatch repair system is required for activation of the S-phase… 

Drug-Sensitive DNA Polymerase δ Reveals a Role for Mismatch Repair in Checkpoint Activation in Yeast

It is proposed that mismatch repair activity produces persisting single-stranded DNA gaps in PAA-treated pol3-L612M cells that are required to increase DNA damage above the threshold needed for checkpoint activation.

Is mismatch repair really required for ionizing radiation–induced DNA damage signaling?

A report by Brown et al. has reopened this discussion by describing the requirement of a functional MMR system for activating the S-phase checkpoint and signaling of ionizing radiation–induced DNA damage signaling.

DNA mismatch repair and the cellular response to UVC radiation

It is proposed that MMR removes mismatches from UVC-induced compound lesions and that the MutSalpha-induced late S/G2-phase arrest is the result of the appearance of DNA single stranded regions arising during this process of MMR.

APE2 is required for ATR-Chk1 checkpoint activation in response to oxidative stress

Evidence is provided showing that hydrogen peroxide triggers checkpoint kinase 1 (Chk1) phosphorylation in an ATR [ataxia-telangiectasia mutated (ATM) and Rad3-related]-dependent but ATM-independent manner in Xenopus egg extracts, indicating that APE2 plays a vital and previously unexpected role in ATR-Chk 1 checkpoint signaling in response to oxidative stress.

MSH2 and ATR form a signaling module and regulate two branches of the damage response to DNA methylation

  • Yi WangJ. Qin
  • Biology, Chemistry
    Proceedings of the National Academy of Sciences of the United States of America
  • 2003
It is reported that MSH2 (MutS homolog 2) protein interacts with the ATR (ATM- and Rad3-related) kinase to form a signaling module and regulate the phosphorylation of Chk1 and SMC1 (structure maintenance of chromosome 1).

DNA mismatch repair proteins promote apoptosis and suppress tumorigenesis in response to UVB irradiation: an in vivo study.

It is proposed that dysfunctional MMR promotes UVB-induced tumorigenesis through reduced apoptotic elimination of damaged epidermal cells through reduction of apoptosis in the epidermis following acute UVB exposure.



The ATM–Chk2–Cdc25A checkpoint pathway guards against radioresistant DNA synthesis

A functional link between ATM, the checkpoint signalling kinase Chk2/Cds1 (Chk2) and Cdc25A is reported, and this mechanism in controlling the S-phase checkpoint is identified as a genomic integrity checkpoint that prevents radioresistant DNA synthesis.

The DNA damage-dependent intra–S phase checkpoint is regulated by parallel pathways

It is concluded that in response to ionizing radiation, phosphorylations of Nbs1 and Chk2 by ATM trigger two parallel branches of the DNA damage-dependent S-phase checkpoint that cooperate by inhibiting distinct steps of DNA replication.

Role of DNA mismatch repair in the cytotoxicity of ionizing radiation.

A new class of DNA-damaging agents whose effects are modulated by the MMR system is identified and may help to elucidate pathways of radiation response in cancer cells.

ATM phosphorylates p95/nbs1 in an S-phase checkpoint pathway

Observations link ATM and p95/nbs1 in a common signalling pathway and provide an explanation for phenotypic similarities in these two diseases.

Loss of DNA mismatch repair imparts defective cdc2 signaling and G(2) arrest responses without altering survival after ionizing radiation.

Although MMR status does not significantly affect the survival of cells after high-dose-rate IR, it seems to regulate the G(2)-M checkpoint and might affect overall mutation rates.

ATM-dependent phosphorylation of nibrin in response to radiation exposure

It is demonstrated that nibrin is phosphorylated within one hour of treatment of cells with IR, and ATM physically interacts with and phosphorylatesnibrin on serine 343 both in vivo and in vitro.

The human MLH1 cDNA complements DNA mismatch repair defects in Mlh1-deficient mouse embryonic fibroblasts.

It is confirmed that hMLH1 has an essential role in the maintenance of genomic stability and the potentiation of 6-TG cytotoxicity and a system for detailed structure/function analysis of the h MLH1 protein is provided.

Human MRE11 is inactivated in mismatch repair‐deficient cancers

MRE11 is identified as a novel and major target for inactivation in mismatch repair‐defective cells and suggest its impairment may contribute to the development of colorectal cancer.

An alkylation-tolerant, mutator human cell line is deficient in strand-specific mismatch repair.

The findings substantiate the idea that strand-specific mismatch repair contributes to alkylation-induced cytotoxicity and imply that this process serves as a barrier to spontaneous transition, transversion, and insertion/deletion mutations in mammalian cells.

hMre11 and hRad50 nuclear foci are induced during the normal cellular response to DNA double-strand breaks

Genetic evidence from Saccharomyces cerevisiae indicating that Mre11-Rad50 have roles distinct from that of Rad51 in DSB repair is supported, and data indicate that hMre 11-hRad50 foci form in response to DNA DSBs and are dependent upon a DNA damage-induced signaling pathway.