Journal ArticleDOI
Sensing DNA Damage Through ATRIP Recognition of RPA-ssDNA Complexes
Lee Zou,Stephen J. Elledge +1 more
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TLDR
The data suggest that RPA-coated ssDNA is the critical structure at sites of DNA damage that recruits the ATR-ATRIP complex and facilitates its recognition of substrates for phosphorylation and the initiation of checkpoint signaling.Abstract:
The function of the ATR (ataxia-telangiectasia mutated- and Rad3-related)-ATRIP (ATR-interacting protein) protein kinase complex is crucial for the cellular response to replication stress and DNA damage. Here, we show that replication protein A (RPA), a protein complex that associates with single-stranded DNA (ssDNA), is required for the recruitment of ATR to sites of DNA damage and for ATR-mediated Chk1 activation in human cells. In vitro, RPA stimulates the binding of ATRIP to ssDNA. The binding of ATRIP to RPA-coated ssDNA enables the ATR-ATRIP complex to associate with DNA and stimulates phosphorylation of the Rad17 protein that is bound to DNA. Furthermore, Ddc2, the budding yeast homolog of ATRIP, is specifically recruited to double-strand DNA breaks in an RPA-dependent manner. A checkpoint-deficient mutant of RPA, rfa1-t11, is defective for recruiting Ddc2 to ssDNA both in vivo and in vitro. Our data suggest that RPA-coated ssDNA is the critical structure at sites of DNA damage that recruits the ATR-ATRIP complex and facilitates its recognition of substrates for phosphorylation and the initiation of checkpoint signaling.read more
Citations
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Journal ArticleDOI
Protein phosphatase 2A-dependent dephosphorylation of replication protein A is required for the repair of DNA breaks induced by replication stress.
TL;DR: It is reported here that in cells recovering from hydroxyurea (HU)-induced genotoxic stress, RPA32 is dephosphorylated by the serine/threonine protein phosphatase 2A (PP2A) and this data indicate that PP2A-mediated R PA32 deph phosphorylation is required for the efficient DNA damage repair.
Journal ArticleDOI
The multi-replication protein A (RPA) system – a new perspective
TL;DR: The composition and biological functions of RPA complexes are reviewed and the multi‐RPA system can be regarded as universal in eukaryotes.
Journal ArticleDOI
The DNA double-strand break response pathway: becoming more BRCAish than ever.
Nicholas S.Y. Ting,Wen-Hwa Lee +1 more
TL;DR: A simple model is provided in an attempt to clarify the role of Brca1 during cellular response to DNA DSB, which has been intimately linked with various aspects of this signaling pathway.
Journal ArticleDOI
The Cytolethal Distending Toxin Effects on Mammalian Cells: A DNA Damage Perspective
TL;DR: The latest results regarding the host cell response to CDT intoxication are reviewed and focus on DNA damage characteristics, cell cycle modulation and cell outcomes.
Journal ArticleDOI
TopBP1 and DNA polymerase alpha-mediated recruitment of the 9-1-1 complex to stalled replication forks: Implications for a replication restart-based mechanism for ATR checkpoint activation
Shan Yan,W. Matthew Michael +1 more
TL;DR: A revised model for ATR activation is presented, and it is speculated that TopBP1-mediated recruitment of pol α and 9-1-1 may couple checkpoint activation to replication restart, when DNA synthesis is blocked on the leading strand of a replication fork.
References
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Journal ArticleDOI
The DNA damage response: putting checkpoints in perspective
TL;DR: The inability to repair DNA damage properly in mammals leads to various disorders and enhanced rates of tumour development, and this work has shown that direct activation of DNA repair networks is needed to correct this problem.
Journal ArticleDOI
Cell cycle checkpoint signaling through the ATM and ATR kinases
TL;DR: These checkpoints contain, as their most proximal signaling elements, sensor proteins that scan chromatin for partially replicated DNA, DNA strand breaks, or other abnormalities, and translate these DNA-derived stimuli into biochemical signals that modulate the functions of specific downstream target proteins.
Journal ArticleDOI
Chk1 is an essential kinase that is regulated by Atr and required for the G2/M DNA damage checkpoint
Qinghua Liu,Saritha Guntuku,Xian Shu Cui,Shuhei Matsuoka,David Cortez,Katsuyuki Tamai,Guangbin Luo,Sandra Carattini-Rivera,Francisco J. DeMayo,Allan Bradley,Lawrence A. Donehower,Stephen J. Elledge +11 more
TL;DR: It is shown that in human cells, Chk1 is phosphorylated on serine 345 (S345) in response to UV, IR, and hydroxyurea (HU).
Journal ArticleDOI
Human DNA Repair Genes
TL;DR: Modulation of DNA repair should lead to clinical applications including improvement of radiotherapy and treatment with anticancer drugs and an advanced understanding of the cellular aging process.
Journal ArticleDOI
REPLICATION PROTEIN A: A Heterotrimeric, Single-Stranded DNA-Binding Protein Required for Eukaryotic DNA Metabolism
TL;DR: Replication protein A (RPA) is a single-stranded DNA-binding protein that is required for multiple processes in eukaryotic DNA metabolism, including DNA replication, DNA repair, and recombination.