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
Cyclin-dependent kinase 2 dependent phosphorylation of ATRIP regulates the G2-M checkpoint response to DNA damage.
TL;DR: ATRIP is aCDK2 substrate, and CDK2-dependent phosphorylation of S224 regulates the ability of ATR-ATRIP to promote cell cycle arrest in response to DNA damage.
Journal ArticleDOI
DNA damage regulates Chk2 association with chromatin.
Jia Li,David F. Stern +1 more
TL;DR: Using chromatin fractionation as well as immunostaining combined with detergent pre-extraction, it is found that a small pool of Chk2 is associated with chromatin prior to DNA damage, and data suggest that DNA damage induces activation of chromatin-bound Chk 2 by a Chromatin-derived signal, and that this results in dissociation of activated Chk1 from chromatin, facilitating further signal amplification and transmission to soluble substrates.
Journal ArticleDOI
The fork and the kinase: A DNA replication tale from a CHK1 perspective
TL;DR: Chk1 is a multifaceted and versatile signaling factor that acts at ongoing forks and replication origins to determine the extent and quality of the cellular response to replication stress.
Journal ArticleDOI
DNA damage checkpoints and cancer.
Midori Shimada,Makoto Nakanishi +1 more
TL;DR: The molecular mechanisms of checkpoint activation in response to DNA damage and the correlation between checkpoint gene mutation and genomic instability are described.
Journal ArticleDOI
The involvement of ataxia-telangiectasia mutated protein activation in nucleotide excision repair-facilitated cell survival with cisplatin treatment.
TL;DR: In this paper, the role of nucleotide excision repair (NER) in cisplatin DNA damage-induced apoptotic cell death using both normal human fibroblasts and NER-defective xeroderma pigmentosum (XP) XPA and XPG cells was studied.
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.