Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
ATM and ATR promote Mre11 dependent restart of collapsed replication forks and prevent accumulation of DNA breaks.
Trenz K
,
Smith E
,
Smith S
,
Costanzo V
.
???displayArticle.abstract???
Ataxia-telangiectasia mutated (ATM), ataxia-telangiectasia Rad3-related (ATR) and the Mre11/Rad50/Nbs1 complex ensure genome stability in response to DNA damage. However, their essential role in DNA metabolism remains unknown. Here we show that ATM and ATR prevent accumulation of DNA double-strand breaks (DSBs) during chromosomal replication. Replicating chromosomes accumulate DSBs in Xenopus laevis egg extracts depleted of ATM and ATR. Addition of ATM and ATR proteins to depleted extracts prevents DSB accumulation by promoting restart of collapsed replication forks that arise during DNA replication. We show that collapsed forks maintain MCM complex but lose Pol epsilon, and that Pol epsilon reloading requires ATM and ATR. Replication fork restart is abolished in Mre11 depleted extracts and is restored by supplementation with recombinant human Mre11/Rad50/Nbs1 complex. Using a novel fluorescence resonance energy transfer-based technique, we demonstrate that ATM and ATR induce Mre11/Rad50/Nbs1 complex redistribution to restarting forks. This study provides direct biochemical evidence that ATM and ATR prevent accumulation of chromosomal abnormalities by promoting Mre11/Rad50/Nbs1 dependent recovery of collapsed replication forks.
Brown,
ATR disruption leads to chromosomal fragmentation and early embryonic lethality.
2000, Pubmed
Brown,
ATR disruption leads to chromosomal fragmentation and early embryonic lethality.
2000,
Pubmed
Byun,
Functional uncoupling of MCM helicase and DNA polymerase activities activates the ATR-dependent checkpoint.
2005,
Pubmed
,
Xenbase
Caldecott,
XRCC1 and DNA strand break repair.
2003,
Pubmed
Caldecott,
DNA single-strand breaks and neurodegeneration.
2004,
Pubmed
Carson,
The Mre11 complex is required for ATM activation and the G2/M checkpoint.
2003,
Pubmed
Casper,
ATR regulates fragile site stability.
2002,
Pubmed
Cha,
ATR homolog Mec1 promotes fork progression, thus averting breaks in replication slow zones.
2002,
Pubmed
Chen,
Development of a fluorescence resonance energy transfer assay for measuring the activity of Streptococcus pneumoniae DNA ligase, an enzyme essential for DNA replication, repair, and recombination.
2002,
Pubmed
Cobb,
DNA polymerase stabilization at stalled replication forks requires Mec1 and the RecQ helicase Sgs1.
2003,
Pubmed
Cortez,
Minichromosome maintenance proteins are direct targets of the ATM and ATR checkpoint kinases.
2004,
Pubmed
Costanzo,
Xenopus cell-free extracts to study DNA damage checkpoints.
2004,
Pubmed
,
Xenbase
Costanzo,
Mre11 assembles linear DNA fragments into DNA damage signaling complexes.
2004,
Pubmed
,
Xenbase
Costanzo,
Reconstitution of an ATM-dependent checkpoint that inhibits chromosomal DNA replication following DNA damage.
2000,
Pubmed
,
Xenbase
Costanzo,
Mre11 protein complex prevents double-strand break accumulation during chromosomal DNA replication.
2001,
Pubmed
,
Xenbase
Dolganov,
Human Rad50 is physically associated with human Mre11: identification of a conserved multiprotein complex implicated in recombinational DNA repair.
1996,
Pubmed
Edwards,
MCM2-7 complexes bind chromatin in a distributed pattern surrounding the origin recognition complex in Xenopus egg extracts.
2002,
Pubmed
,
Xenbase
Falck,
Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage.
2005,
Pubmed
Haber,
The many interfaces of Mre11.
1998,
Pubmed
Hopfner,
Structural biochemistry and interaction architecture of the DNA double-strand break repair Mre11 nuclease and Rad50-ATPase.
2001,
Pubmed
Jazayeri,
ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks.
2006,
Pubmed
Kang,
Targeted disruption of NBS1 reveals its roles in mouse development and DNA repair.
2002,
Pubmed
Li,
Absence of BLM leads to accumulation of chromosomal DNA breaks during both unperturbed and disrupted S phases.
2004,
Pubmed
,
Xenbase
Li,
Cdt1 downregulation by proteolysis and geminin inhibition prevents DNA re-replication in Xenopus.
2005,
Pubmed
,
Xenbase
Lopes,
Multiple mechanisms control chromosome integrity after replication fork uncoupling and restart at irreparable UV lesions.
2006,
Pubmed
Lopes,
The DNA replication checkpoint response stabilizes stalled replication forks.
2001,
Pubmed
Lucca,
Checkpoint-mediated control of replisome-fork association and signalling in response to replication pausing.
2004,
Pubmed
Luciani,
Characterization of a novel ATR-dependent, Chk1-independent, intra-S-phase checkpoint that suppresses initiation of replication in Xenopus.
2004,
Pubmed
,
Xenbase
Luo,
Disruption of mRad50 causes embryonic stem cell lethality, abnormal embryonic development, and sensitivity to ionizing radiation.
1999,
Pubmed
Marheineke,
Control of replication origin density and firing time in Xenopus egg extracts: role of a caffeine-sensitive, ATR-dependent checkpoint.
2004,
Pubmed
,
Xenbase
McHugh,
Repair of intermediate structures produced at DNA interstrand cross-links in Saccharomyces cerevisiae.
2000,
Pubmed
Mirzoeva,
DNA replication-dependent nuclear dynamics of the Mre11 complex.
2003,
Pubmed
Morgan,
p53 and ATM: cell cycle, cell death, and cancer.
1997,
Pubmed
Murray,
Cell cycle extracts.
1991,
Pubmed
O'Driscoll,
A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome.
2003,
Pubmed
Petrini,
Isolation and characterization of the human MRE11 homologue.
1995,
Pubmed
Pommier,
Camptothecins and topoisomerase I: a foot in the door. Targeting the genome beyond topoisomerase I with camptothecins and novel anticancer drugs: importance of DNA replication, repair and cell cycle checkpoints.
2004,
Pubmed
Saleh-Gohari,
Spontaneous homologous recombination is induced by collapsed replication forks that are caused by endogenous DNA single-strand breaks.
2005,
Pubmed
Sancar,
Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints.
2004,
Pubmed
Shechter,
ATR and ATM regulate the timing of DNA replication origin firing.
2004,
Pubmed
,
Xenbase
Shiloh,
ATM: genome stability, neuronal development, and cancer cross paths.
2001,
Pubmed
Sogo,
Fork reversal and ssDNA accumulation at stalled replication forks owing to checkpoint defects.
2002,
Pubmed
Stewart,
The DNA double-strand break repair gene hMRE11 is mutated in individuals with an ataxia-telangiectasia-like disorder.
1999,
Pubmed
Sørensen,
The cell-cycle checkpoint kinase Chk1 is required for mammalian homologous recombination repair.
2005,
Pubmed
Tercero,
A central role for DNA replication forks in checkpoint activation and response.
2003,
Pubmed
Uziel,
Requirement of the MRN complex for ATM activation by DNA damage.
2003,
Pubmed
Waga,
DNA polymerase epsilon is required for coordinated and efficient chromosomal DNA replication in Xenopus egg extracts.
2001,
Pubmed
,
Xenbase
Xiao,
Conditional gene targeted deletion by Cre recombinase demonstrates the requirement for the double-strand break repair Mre11 protein in murine embryonic stem cells.
1997,
Pubmed
Yoo,
Mcm2 is a direct substrate of ATM and ATR during DNA damage and DNA replication checkpoint responses.
2004,
Pubmed
,
Xenbase
You,
ATM activation and its recruitment to damaged DNA require binding to the C terminus of Nbs1.
2005,
Pubmed
,
Xenbase
Zou,
Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes.
2003,
Pubmed
de Jager,
Human Rad50/Mre11 is a flexible complex that can tether DNA ends.
2001,
Pubmed
