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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Human single-stranded DNA binding protein 1 (hSSB1/NABP2) is required for the stability and repair of stalled replication forks
Emma Bolderson,Eva Petermann,Laura V. Croft,Amila Suraweera,Raj K. Pandita,Tej K. Pandita,Thomas Helleday,Kum Kum Khanna,Derek J. Richard +8 more
TL;DR: In this paper, the single-stranded DNA binding protein, hSSB1/NABP2, was shown to relocate to hydroxyurea (HU)-damaged replication forks where it is required for ATR and Chk1 activation and recruitment of Mre11 and Rad51.
Journal ArticleDOI
ATR is a multifunctional regulator of male mouse meiosis
Alexander Widger,Shantha K. Mahadevaiah,Julian Lange,Elias ElInati,Jasmin Zohren,Takayuki Hirota,Sarai Pacheco,Andros Maldonado-Linares,Marcello Stanzione,Obah A. Ojarikre,Valdone Maciulyte,Dirk G. de Rooij,Attila Tóth,Ignasi Roig,Scott Keeney,James M. A. Turner +15 more
TL;DR: It is demonstrated, using a tissue-specific knockout approach, that ATR is also essential for male meiosis in mouse, regulating meiotic recombination and synapsis, and is revealed as a critical regulator of mouse meiosis.
Journal ArticleDOI
Crosstalk between Phosphoinositide 3-kinase/Akt signaling pathway with DNA damage response and oxidative stress in cancer.
Ansar Karimian,Ansar Karimian,Sayed Mostafa Mir,Sayed Mostafa Mir,Hadi Parsian,Sona Refieyan,Mohammad Mirza-Aghazadeh-Attari,Bahman Yousefi,Bahman Yousefi,Bahman Yousefi,Maryam Majidinia +10 more
TL;DR: The most recent discoveries on the involvement of PI3K/Akt signaling pathway in cancer development, as well as stimulation of some important signaling networks involved in the maintenance of cellular homeostasis upon DNA damage are discussed.
Journal ArticleDOI
Multifaceted Fanconi Anemia Signaling.
TL;DR: The characteristics of FA functions are discussed and current perspectives regarding the genetics of FA are expanded, indicating that FA plays a role in a myriad of molecular and cellular processes.
Journal ArticleDOI
A novel interplay between the Fanconi anemia core complex and ATR-ATRIP kinase during DNA cross-link repair.
Junya Tomida,Akiko Itaya,Akiko Itaya,Tomoko Shigechi,Tomoko Shigechi,Junya Unno,Emi Uchida,Masae Ikura,Yuji Masuda,Shun Matsuda,Jun Adachi,Masahiko Kobayashi,Amom Ruhikanta Meetei,Yoshihiko Maehara,Ken Ichi Yamamoto,Kenji Kamiya,Akira Matsuura,Tomonari Matsuda,Tsuyoshi Ikura,Masamichi Ishiai,Minoru Takata +20 more
TL;DR: Following cellular exposure to DNA cross-linking damage, the FA core complex enhances binding and localization of ATRIP within damaged chromatin, and new aspects of the interplay between regulation of ATR-ATRIP kinase and activation of the FA pathway are revealed.
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.