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
Chk1 in the DNA damage response: conserved roles from yeasts to mammals.
Yinhuai Chen,Yolanda Sanchez +1 more
TL;DR: What is known about Chk1 activation and what downstream factors are regulated by Chk2 to counter replication blocks and DNA damage induced by UV, IR, and other genotoxic agents are discussed.
Journal ArticleDOI
Claspin Operates Downstream of TopBP1 To Direct ATR Signaling towards Chk1 Activation
TL;DR: It is shown that TopBP1 tightly colocalizes with ATR in distinct nuclear subcompartments generated by DNA damage, and that Claspin operates downstream of Top BP1 to selectively regulate the Chk1-controlled branch of the genotoxic stress response.
Journal ArticleDOI
Identification and evaluation of a potent novel ATR inhibitor, NU6027, in breast and ovarian cancer cell lines
A. Peasland,Lan Z. Wang,Emily J. Rowling,Suzanne Kyle,Tao Chen,A. Hopkins,W. A. Cliby,Jann N. Sarkaria,Gary S. Beale,Richard J. Edmondson,Nicola J. Curtin +10 more
TL;DR: NU6027 inhibits ATR, impairing G2/M arrest and homologous recombination thus increasing sensitivity to DNA-damaging agents and PARP inhibitors and provides proof of concept data for clinical development of ATR inhibitors.
Journal ArticleDOI
ETAA1 acts at stalled replication forks to maintain genome integrity
Thomas E. Bass,Jessica W. Luzwick,Gina Kavanaugh,Clinton Carroll,Huzefa Dungrawala,Gloria G. Glick,Michael D. Feldkamp,D. Reid Putney,Walter J. Chazin,David Cortez +9 more
TL;DR: In this article, the authors identified ETAA1 as a replication stress response protein in two proteomic screens and showed that ETAA-deficient cells accumulate double-strand breaks, sister chromatid exchanges, and other hallmarks of genome instability.
Journal ArticleDOI
Seckel syndrome exhibits cellular features demonstrating defects in the ATR-signalling pathway
Gemma K. Alderton,Hans Joenje,Raymonda Varon,Anders D. Børglum,Penny A. Jeggo,Mark O'Driscoll +5 more
TL;DR: It is concluded that Seckel syndrome represents a further damage response disorder that is uniquely associated with defects in the ATR-signalling pathway resulting in failed checkpoint arrest following exposure to replication fork stalling.
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.