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
Human single-stranded DNA binding proteins: guardians of genome stability
TL;DR: This review summarizes the current understanding of these human SSBs in DNA damage repair and in cell-cycle checkpoint activation following DNA damage, as well as their relationships with cancer.
Journal ArticleDOI
Chromatin Remodeling and Epigenetic Regulation in Plant DNA Damage Repair.
TL;DR: This review examines how DDR and DNA repair machineries are concertedly regulated in Arabidopsis thaliana by a variety of epigenetic modifiers directing chromatin remodeling and epigenetic modification.
Journal ArticleDOI
DNA-PKcs is required to maintain stability of Chk1 and Claspin for optimal replication stress response
TL;DR: The investigation reveals that DNA-PKcs is required to maintain Chk1–Claspin complex stability and transcriptional regulation of Claspin expression, and suggests thatDNA- PKcs facilitates ATR-Chk1 signaling pathway in response to replication stress.
Journal ArticleDOI
Small molecule inhibitor of the RPA70 N-terminal protein interaction domain discovered using in silico and in vitro methods.
TL;DR: Through the use of high-throughput screening of 1500 compounds, a small molecule inhibitor is identified, 15-carboxy- 13-isopropylatis-13-ene-17,18-dioic acid (NSC15520), that inhibited both the binding of Rad9-GST and p53-G ST fusion proteins to the RPA N-terminal DNA binding domain (DBD), interactions that are essential for robust DNA damage signaling.
Journal ArticleDOI
The increase of cell-membranous phosphatidylcholines containing polyunsaturated fatty acid residues induces phosphorylation of p53 through activation of ATR.
TL;DR: It is established that cells can regulate the levels of polyunsaturated fatty acids in phospholipids through iPLA2-mediated deacylation of PCs and disruption of this regulation increases the proportions of PCs containing polyuns saturated fatty acids and activates the ATR-p53 signalling pathway.
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.