One of the key aims of cancer research is to understand how cells detect and repair double-strand breaks (DSBs) in DNA. DSBs are important because they are a major source of genome instability that is a hallmark of cancer. Moreover, many of the most widely used and effective anti-cancer therapies use targeted irradiation or chemotherapeutics to create DSBs, which preferentially kill cancer cells. The Mre11-Rad50-Nbs1 (MRN) protein complex, its repair cofactor Ctp1/CtIP/Sae2, and its checkpoint signaling cofactor Tel1/ATM, have evolutionary conserved functions that are crucial for detecting and repairing DSBs, and for activating the DNA damage checkpoint that arrests cell division. Fission yeast mutants lacking MRN or Ctp1 are unable to repair DSBs, and therefore display genomic instability and are acutely sensitive to clastogens. Human genetic diseases that partially impair the functions of these proteins cause genome instability syndromes. Notably, hypomorphic mutations in human Nbs1 cause microcephaly, developmental abnormalities, immunodeficiency, radiation sensitivity and cancer predisposition. Recent studies revealed that Nbs1 functions as a molecular tether that links Ctp1 and Tel1 to the Mre11-Rad50 complex. In this project, we propose to use genetic, cell biological and in vivo assays to characterize the functional interactions between the MRN complex and Ctp1 at DSBs formed by replication fork collapse. These studies will improve the conceptual understanding of how mutations in human Nbs1 cause cancer, and in doing so enhance opportunities for developing new strategies for cancer prevention and treatment.

Public Health Relevance

The Mre11-Rad50-Nbs1 protein complex, Ctp1 (CtIP) and Tel1 (ATM) protect genome integrity and prevent cancer causing mutations by detecting, signaling and repairing DNA double-strand breaks. This project will define the functional interactions amongst these proteins, and thereby identify new potential anti- cancer strategies. !

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Molecular Genetics B Study Section (MGB)
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Pelroy, Richard
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Scripps Research Institute
La Jolla
United States
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Limbo, Oliver; Yamada, Yoshiki; Russell, Paul (2018) Mre11-Rad50-dependent activity of ATM/Tel1 at DNA breaks and telomeres in the absence of Nbs1. Mol Biol Cell 29:1389-1399
Reubens, Michael C; Rozenzhak, Sophie; Russell, Paul (2017) Multi-BRCT Domain Protein Brc1 Links Rhp18/Rad18 and ?H2A To Maintain Genome Stability during S Phase. Mol Cell Biol 37:
Guo, Lan; Ganguly, Abantika; Sun, Lingling et al. (2016) Global Fitness Profiling Identifies Arsenic and Cadmium Tolerance Mechanisms in Fission Yeast. G3 (Bethesda) 6:3317-3333
Jensen, Kristi L; Russell, Paul (2016) Ctp1-dependent clipping and resection of DNA double-strand breaks by Mre11 endonuclease complex are not genetically separable. Nucleic Acids Res 44:8241-9
Petersen, Janni; Russell, Paul (2016) Growth and the Environment of Schizosaccharomyces pombe. Cold Spring Harb Protoc 2016:pdb.top079764
Sánchez, Arancha; Russell, Paul (2015) Ku stabilizes replication forks in the absence of Brc1. PLoS One 10:e0126598
Mejia-Ramirez, Eva; Limbo, Oliver; Langerak, Petra et al. (2015) Critical Function of ?H2A in S-Phase. PLoS Genet 11:e1005517
Sánchez, Arancha; Roguev, Assen; Krogan, Nevan J et al. (2015) Genetic Interaction Landscape Reveals Critical Requirements for Schizosaccharomyces pombe Brc1 in DNA Damage Response Mutants. G3 (Bethesda) 5:953-62
Wang, Lanfeng; Limbo, Oliver; Fei, Jia et al. (2014) Regulation of the Rhp26ERCC6/CSB chromatin remodeler by a novel conserved leucine latch motif. Proc Natl Acad Sci U S A 111:18566-71
Wei, Yi; Wang, Hai-Tao; Zhai, Yonggong et al. (2014) Mdb1, a fission yeast homolog of human MDC1, modulates DNA damage response and mitotic spindle function. PLoS One 9:e97028

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