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
Phosphatase type 2A-dependent and -independent pathways for ATR phosphorylation of Chk1.
TL;DR: It is demonstrated here that of these three agents only Vpr requires protein phosphatase type 2A (PP2A) to activate ATR for Chk1-Ser345 phosphorylation, and downregulations decreased the Vpr-induced, ATR-dependent phosphorylations of Cdk1-Tyr15 and Chk 1-Ser 345.
Journal ArticleDOI
ATR controls cellular adaptation to hypoxia through positive regulation of hypoxia-inducible factor 1 (HIF-1) expression.
Frédérique Fallone,Sébastien Britton,Sébastien Britton,Laurence Nieto,Laurence Nieto,Bernard Salles,Bernard Salles,Bernard Salles,Catherine Muller,Catherine Muller +9 more
TL;DR: The data show a new function for ATR in cellular adaptation to hypoxia through regulation of HIF-1α translation, which offers new prospect for cancer therapy using ATR inhibitors with the potential to decrease cellular adaptation in hypoxic tumors.
Journal ArticleDOI
Molecular Cooperation between the Werner Syndrome Protein and Replication Protein A in Relation to Replication Fork Blockage
TL;DR: In this paper, the physical and functional interaction between the RecQ helicase family member Werner syndrome protein (WRN) and RPA was examined in relation to replication fork blockage.
Journal ArticleDOI
Optical double-image cryptography based on diffractive imaging with a laterally-translated phase grating
TL;DR: A method using structured-illumination-based diffractive imaging with a laterally-translated phase grating for optical double-image cryptography with an iterative retrieval algorithm to extract plaintexts from the ciphertexts is proposed.
Journal ArticleDOI
Translesion DNA Synthesis in Cancer: Molecular Mechanisms and Therapeutic Opportunities
Maroof K. Zafar,Robert L. Eoff +1 more
TL;DR: Mechanisms of DDT, misregulation of TLS in cancer, and the potential for targeting these pathways as a means of improving cancer therapies are discussed.
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.