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In the presence of double-stranded DNA breaks (DSBs), the activation of ATR is achieved by the ability of ATM to phosphorylate TopBP1 on serine 1131, which leads to an enhancement of the interaction between ATR and TopBP1. In Xenopus egg extracts, the Mre11-Rad50-Nbs1 (MRN) complex is additionally required to bridge ATM and TopBP1 together. In this report, we show that CtIP, which is recruited to DSB-containing chromatin, interacts with both TopBP1 and Nbs1 in a damage-dependent manner. An N-terminal region containing the first two BRCT repeats of TopBP1 is essential for the interaction with CtIP. Furthermore, two distinct regions in the N-terminus of CtIP participate in establishing the association between CtIP and TopBP1. The first region includes two adjacent putative ATM/ATR phosphorylation sites on serines 273 and 275. Secondly, binding is diminished when an MRN-binding region spanning residues 25-48 is deleted, indicative of a role for the MRN complex in mediating this interaction. This was further evidenced by a decrease in the interaction between CtIP and TopBP1 in Nbs1-depleted extracts and a reciprocal decrease in the binding of Nbs1 to TopBP1 in the absence of CtIP, suggestive of the formation of a complex containing CtIP, TopBP1, and the MRN complex. When CtIP is immunodepleted from egg extracts, the activation of the response to DSBs is compromised and the levels of ATR, TopBP1, and Nbs1 on damaged chromatin are reduced. Thus, CtIP interacts with TopBP1 in a damage-stimulated, MRN-dependent manner during the activation of ATR in response to DSBs.
Abraham,
Cell cycle checkpoint signaling through the ATM and ATR kinases.
2001, Pubmed
Abraham,
Cell cycle checkpoint signaling through the ATM and ATR kinases.
2001,
Pubmed Byun,
Functional uncoupling of MCM helicase and DNA polymerase activities activates the ATR-dependent checkpoint.
2005,
Pubmed
,
Xenbase Caldecott,
Cell signaling. The BRCT domain: signaling with friends?
2003,
Pubmed Chen,
Cell cycle-dependent complex formation of BRCA1.CtIP.MRN is important for DNA double-strand break repair.
2008,
Pubmed Cimprich,
ATR: an essential regulator of genome integrity.
2008,
Pubmed Cortez,
ATR and ATRIP: partners in checkpoint signaling.
2001,
Pubmed Farah,
Ctp1 and Exonuclease 1, alternative nucleases regulated by the MRN complex, are required for efficient meiotic recombination.
2009,
Pubmed Fusco,
Molecular cloning and characterization of a novel retinoblastoma-binding protein.
1998,
Pubmed Halazonetis,
An oncogene-induced DNA damage model for cancer development.
2008,
Pubmed Hartsuiker,
Distinct requirements for the Rad32(Mre11) nuclease and Ctp1(CtIP) in the removal of covalently bound topoisomerase I and II from DNA.
2009,
Pubmed Hashimoto,
The phosphorylated C-terminal domain of Xenopus Cut5 directly mediates ATR-dependent activation of Chk1.
2006,
Pubmed
,
Xenbase Jazayeri,
ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks.
2006,
Pubmed Kastan,
Cell-cycle checkpoints and cancer.
2004,
Pubmed Kumagai,
Claspin, a novel protein required for the activation of Chk1 during a DNA replication checkpoint response in Xenopus egg extracts.
2000,
Pubmed
,
Xenbase Kumagai,
The Xenopus Chk1 protein kinase mediates a caffeine-sensitive pathway of checkpoint control in cell-free extracts.
1998,
Pubmed
,
Xenbase Kumagai,
TopBP1 activates the ATR-ATRIP complex.
2006,
Pubmed
,
Xenbase Lavin,
Ataxia-telangiectasia: from a rare disorder to a paradigm for cell signalling and cancer.
2008,
Pubmed Lee,
The Rad9-Hus1-Rad1 checkpoint clamp regulates interaction of TopBP1 with ATR.
2007,
Pubmed
,
Xenbase Lee,
Claspin, a Chk1-regulatory protein, monitors DNA replication on chromatin independently of RPA, ATR, and Rad17.
2003,
Pubmed
,
Xenbase Lee,
Rad17 plays a central role in establishment of the interaction between TopBP1 and the Rad9-Hus1-Rad1 complex at stalled replication forks.
2010,
Pubmed
,
Xenbase Lengsfeld,
Sae2 is an endonuclease that processes hairpin DNA cooperatively with the Mre11/Rad50/Xrs2 complex.
2007,
Pubmed Li,
Functional link of BRCA1 and ataxia telangiectasia gene product in DNA damage response.
2000,
Pubmed Limbo,
Ctp1 is a cell-cycle-regulated protein that functions with Mre11 complex to control double-strand break repair by homologous recombination.
2007,
Pubmed Mimitou,
DNA end resection: many nucleases make light work.
2009,
Pubmed Mimitou,
Sae2, Exo1 and Sgs1 collaborate in DNA double-strand break processing.
2008,
Pubmed Mordes,
TopBP1 activates ATR through ATRIP and a PIKK regulatory domain.
2008,
Pubmed Murray,
Cell cycle extracts.
1991,
Pubmed Nakamura,
Collaborative action of Brca1 and CtIP in elimination of covalent modifications from double-strand breaks to facilitate subsequent break repair.
2010,
Pubmed Negrini,
Genomic instability--an evolving hallmark of cancer.
2010,
Pubmed Nyberg,
Toward maintaining the genome: DNA damage and replication checkpoints.
2002,
Pubmed Rodriguez,
Phosphopeptide binding specificities of BRCA1 COOH-terminal (BRCT) domains.
2003,
Pubmed Sancar,
Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints.
2004,
Pubmed Sartori,
Human CtIP promotes DNA end resection.
2007,
Pubmed Schaeper,
Interaction between a cellular protein that binds to the C-terminal region of adenovirus E1A (CtBP) and a novel cellular protein is disrupted by E1A through a conserved PLDLS motif.
1998,
Pubmed Shiotani,
Single-stranded DNA orchestrates an ATM-to-ATR switch at DNA breaks.
2009,
Pubmed Takeda,
Ctp1/CtIP and the MRN complex collaborate in the initial steps of homologous recombination.
2007,
Pubmed Toledo,
ATR signaling can drive cells into senescence in the absence of DNA breaks.
2008,
Pubmed Uziel,
Requirement of the MRN complex for ATM activation by DNA damage.
2003,
Pubmed Wu-Baer,
Effect of DNA damage on a BRCA1 complex.
2001,
Pubmed Yanow,
Xenopus Drf1, a regulator of Cdc7, displays checkpoint-dependent accumulation on chromatin during an S-phase arrest.
2003,
Pubmed
,
Xenbase Yoo,
The Mre11-Rad50-Nbs1 complex mediates activation of TopBP1 by ATM.
2009,
Pubmed
,
Xenbase Yoo,
Mcm2 is a direct substrate of ATM and ATR during DNA damage and DNA replication checkpoint responses.
2004,
Pubmed
,
Xenbase Yoo,
Adaptation of a DNA replication checkpoint response depends upon inactivation of Claspin by the Polo-like kinase.
2004,
Pubmed
,
Xenbase Yoo,
Ataxia-telangiectasia mutated (ATM)-dependent activation of ATR occurs through phosphorylation of TopBP1 by ATM.
2007,
Pubmed
,
Xenbase You,
CtIP links DNA double-strand break sensing to resection.
2009,
Pubmed
,
Xenbase Yu,
BRCA1 ubiquitinates its phosphorylation-dependent binding partner CtIP.
2006,
Pubmed Yu,
DNA damage-induced cell cycle checkpoint control requires CtIP, a phosphorylation-dependent binding partner of BRCA1 C-terminal domains.
2004,
Pubmed Yu,
The C-terminal (BRCT) domains of BRCA1 interact in vivo with CtIP, a protein implicated in the CtBP pathway of transcriptional repression.
1998,
Pubmed Yuan,
N terminus of CtIP is critical for homologous recombination-mediated double-strand break repair.
2009,
Pubmed Yun,
CtIP-BRCA1 modulates the choice of DNA double-strand-break repair pathway throughout the cell cycle.
2009,
Pubmed Zhu,
Sgs1 helicase and two nucleases Dna2 and Exo1 resect DNA double-strand break ends.
2008,
Pubmed Zou,
Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes.
2003,
Pubmed
