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
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Journal ArticleDOI
p300/CREB-binding Protein Interacts with ATR and Is Required for the DNA Replication Checkpoint
TL;DR: It is demonstrated that complexes containing p300/CBP and ATR can be detected in mammalian cells, and that the downstream kinase CHK1 fails to be phosphorylated in response to stalled DNA replication in cells that lack p300-CBP.
Journal ArticleDOI
The management of DNA double-strand breaks in mitotic G2, and in mammalian meiosis viewed from a mitotic G2 perspective.
TL;DR: This work attempts to summarise the substantial recent progress in understanding the checkpoint management of HRR in mitosis and then goes on to use this information as a framework for understanding the presumed checkpoints management ofHRR in mammalian meiosis.
Journal ArticleDOI
Treacle controls the nucleolar response to rDNA breaks via TOPBP1 recruitment and ATR activation
Clémence Mooser,Ioanna-Eleni Symeonidou,Pia-Amata Leimbacher,Alison Ribeiro,Ann-Marie K. Shorrocks,Stephanie Jungmichel,Sara Larsen,Katja Knechtle,Arti Jasrotia,Diana Zurbriggen,Alain Jeanrenaud,Colin Leikauf,Daniel Fink,Michael L. Nielsen,Andrew N. Blackford,Andrew N. Blackford,Manuel Stucki +16 more
TL;DR: It is shown that the nucleolar response to rDNA breaks is dependent on both ATM and ATR activity, and that TOPBP1 recruitment is mediated by phosphorylation-dependent interactions between three of its BRCT domains and conserved phosphorylated Ser/Thr residues at the C-terminus of theucleolar phosphoprotein Treacle.
Journal ArticleDOI
Distinct functions of POT1 at telomeres.
Katharine S. Barrientos,Megan F. Kendellen,Brian D. Freibaum,Blaine N. Armbruster,Katherine T. Etheridge,Christopher M. Counter +5 more
TL;DR: It is found that the telomeric ssDNA-binding activity and binding to TPP1 are required in cis for POT1 to protect telomeres and inhibit the localization of RPA, which can function as a DNA damage sensor, to telomere.
Journal ArticleDOI
Accessing the Inaccessible: The Organization, Transcription, Replication, and Repair of Heterochromatin in Plants
Wei Feng,Scott D. Michaels +1 more
TL;DR: The maintenance of heterochromatin requires a careful balancing act of access and exclusion, which is achieved through the action of a host of interrelated pathways.
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.