Human CtIP promotes DNA end resection

By A. Sartori, C. Lukas, J. Coates, M. Mistrik, Shuang Fu, J. Bartek, R. Baer, J. Lukas, Stephen P. Jackson. Nature, 2007

1,440 citations recorded by the source corpus.

In the S and G2 phases of the cell cycle, DNA double-strand breaks (DSBs) are processed into single-stranded DNA, triggering ATR-dependent checkpoint signalling and DSB repair by homologous recombination. Previous work has implicated the MRE11 complex in such DSB-processing events. Here, we show that the human CtIP (RBBP8) protein confers resistance to DSB-inducing agents and is recruited to DSBs exclusively in the S and G2 cell-cycle phases. Moreover, we reveal that CtIP is required for DSB resection, and thereby for recruitment of replication protein A (RPA) and the protein kinase ATR to DSBs, and for the ensuing ATR activation. Furthermore, we establish that CtIP physically and functionally interacts with the MRE11 complex, and that both CtIP and MRE11 are required for efficient homologous recombination. Finally, we reveal that CtIP has sequence homology with Sae2, which is involved in MRE11-dependent DSB processing in yeast. These findings establish evolutionarily conserved roles for CtIP-like proteins in controlling DSB resection, checkpoint signalling and homologous recombination.

Subfields: Cell Biology, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/23e357a4e809a78be993ade66474861e6c39802c

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cell Biology

1. Stephen P. Jackson
2. L. Marácz
3. F. Grin
4. N. Pokorn
5. G. Ira
6. Sang Eun Lee
7. W. Chung
8. Zhu Zhu

In Molecular Biology

1. Stephen P. Jackson
2. Thomas Helleday
3. J. Haber
4. M. Jasin
5. S. Polo
6. L. Marácz
7. F. Grin
8. N. Pokorn

In Oncology

1. L. Marácz
2. F. Grin
3. N. Pokorn
4. S. Boulton
5. J. Haber
6. S. Polo
7. L. Zou
8. Alexandre Maréchal

Citations in the corpus

• BLM-DNA2-RPA-MRN and EXO1-BLM-RPA-MRN constitute two DNA end resection machineries for human DNA break repair. (2011, background): “The functions of the human homologs of yeast MRX and Sae2 (MRN and CtIP) are also essential for processing blocked DNA ends (Sartori et al. 2007; Buis et al. 2008).”
• Homologous recombination and human health: the roles of BRCA1, BRCA2 and associated proteins (2015, background): “Possibly, other proteins target CtIP to damage sites (Daugaard et al. 2012).”
• Sources of DNA double-strand breaks and models of recombinational DNA repair. (2014, background): “Analogous machinery is found in mammalian cells, in which Sae2’s ortholog, CtIP, plays a central role and Sgs1’s ortholog, BLM helicase, appears to be coupled with both EXO1 and DNA2 (Sartori et al. 2007; Nimonkar et al. 2011; Sun et al. 2012).”
• Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications. (2011, background): “…of the cell cycle stage, focus formation by others—including CtIP, RPA, ATRIP–ATR, BRCA1, and RAD51—takes place effectively only in association with ssDNA formation by DNA end resection in S/G2 cells (Lisby et al. 2004; Bekker-Jensen et al. 2006; Jazayeri et al. 2006; Sartori et al. 2007).”
• Regulation of homologous recombination in eukaryotes (2010, result): “These observations are mirrored by results from human cells, where CtIP, the human homolog of Sae2, is also required for DSB resection (130).”
• Chapter 1. General introduction (2015, positive): “In mammals, CtIP is also found to regulate DSB resection by interaction with MRN and BRCA1 in the S/G2 phases (113).”
• DNA helicases Sgs1 and BLM promote DNA double-strand break resection. (2008, methodology): “Thus, we used siRNA treatment to deplete BLM, EXO1, or both BLM and EXO1 from U2OS cells, and then exposed depleted cells to Camptothecin for 1 h to induce DSB formation (Camptothecin was used because resection is needed for repair of Camptothecininduced DSBs and because such DSBs occur in S phase, ”
• The MRE11 complex: starting from the ends (2011, background): “The available evidence in mammalian cells suggests that the MRE11 complex, in conjunction with CtIP, the mammalian orthologue of Sae2 and Ctp1, mediates analogous functions in DSB resectio”
• Regulation of DNA repair throughout the cell cycle (2008, background): “Recently, both the fission yeast protein Ctp1 and its mammalian orthologue CtIP were shown to operate cooperatively with the MRN complex exclusively during the S and G2 phases of the cell cycle to promote DSB resection and H”
• PARP is activated at stalled forks to mediate Mre11‐dependent replication restart and recombination (2009, background): “It has been shown earlier that Mre11, part of the Mre11/RAD50/Nbs1 complex and involved in DNA resection to promote HR (Sartori et al, 2007; Buis et al, 2008), has a function in the restart of damaged replica- tion forks (Trenz et al, 2006).”
• DNA damage sensing by the ATM and ATR kinases. (2013, background): “Consistent with the idea that DSB resection is important for ATR activation, depletion, or inactivation of ATM, Mre11, CtIP, Exo1, and Dna2 all lead to diminished ATR responses to DSBs (Fig.”
• Repair of strand breaks by homologous recombination. (2013, background): “Overall, these results are consistent with an upstream role in HR for BRCA1/CtIP in promoting end resection, which is suppressed by 53BP1/RIF1, but a downstream role in HR for Rad51/BRCA2 in strand invasion.”