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The MRX Complex Ensures NHEJ Fidelity through Multiple Pathways Including Xrs2-FHA-Dependent Tel1 Activation.
PLoS Genet. 2016 Mar; 12(3):e1005942.PG

Abstract

Because DNA double-strand breaks (DSBs) are one of the most cytotoxic DNA lesions and often cause genomic instability, precise repair of DSBs is vital for the maintenance of genomic stability. Xrs2/Nbs1 is a multi-functional regulatory subunit of the Mre11-Rad50-Xrs2/Nbs1 (MRX/N) complex, and its function is critical for the primary step of DSB repair, whether by homologous recombination (HR) or non-homologous end joining. In human NBS1, mutations result truncation of the N-terminus region, which contains a forkhead-associated (FHA) domain, cause Nijmegen breakage syndrome. Here we show that the Xrs2 FHA domain of budding yeast is required both to suppress the imprecise repair of DSBs and to promote the robust activation of Tel1 in the DNA damage response pathway. The role of the Xrs2 FHA domain in Tel1 activation was independent of the Tel1-binding activity of the Xrs2 C terminus, which mediates Tel1 recruitment to DSB ends. Both the Xrs2 FHA domain and Tel1 were required for the timely removal of the Ku complex from DSB ends, which correlates with a reduced frequency of imprecise end-joining. Thus, the Xrs2 FHA domain and Tel1 kinase work in a coordinated manner to maintain DSB repair fidelity.

Authors+Show Affiliations

Department of Integrated Protein Functions, Institute for Protein Research, Osaka University, Suita, Osaka, Japan. Department of Biological Science, Graduate School of Science, Osaka University, Suita, Osaka, Japan.Department of Integrated Protein Functions, Institute for Protein Research, Osaka University, Suita, Osaka, Japan.Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.Department of Integrated Protein Functions, Institute for Protein Research, Osaka University, Suita, Osaka, Japan. Department of Biological Science, Graduate School of Science, Osaka University, Suita, Osaka, Japan.Department of Integrated Protein Functions, Institute for Protein Research, Osaka University, Suita, Osaka, Japan.Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.Department of Integrated Protein Functions, Institute for Protein Research, Osaka University, Suita, Osaka, Japan. Department of Biological Science, Graduate School of Science, Osaka University, Suita, Osaka, Japan. Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26990569

Citation

Iwasaki, Daichi, et al. "The MRX Complex Ensures NHEJ Fidelity Through Multiple Pathways Including Xrs2-FHA-Dependent Tel1 Activation." PLoS Genetics, vol. 12, no. 3, 2016, pp. e1005942.
Iwasaki D, Hayashihara K, Shima H, et al. The MRX Complex Ensures NHEJ Fidelity through Multiple Pathways Including Xrs2-FHA-Dependent Tel1 Activation. PLoS Genet. 2016;12(3):e1005942.
Iwasaki, D., Hayashihara, K., Shima, H., Higashide, M., Terasawa, M., Gasser, S. M., & Shinohara, M. (2016). The MRX Complex Ensures NHEJ Fidelity through Multiple Pathways Including Xrs2-FHA-Dependent Tel1 Activation. PLoS Genetics, 12(3), e1005942. https://doi.org/10.1371/journal.pgen.1005942
Iwasaki D, et al. The MRX Complex Ensures NHEJ Fidelity Through Multiple Pathways Including Xrs2-FHA-Dependent Tel1 Activation. PLoS Genet. 2016;12(3):e1005942. PubMed PMID: 26990569.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The MRX Complex Ensures NHEJ Fidelity through Multiple Pathways Including Xrs2-FHA-Dependent Tel1 Activation. AU - Iwasaki,Daichi, AU - Hayashihara,Kayoko, AU - Shima,Hiroki, AU - Higashide,Mika, AU - Terasawa,Masahiro, AU - Gasser,Susan M, AU - Shinohara,Miki, Y1 - 2016/03/18/ PY - 2015/06/25/received PY - 2016/02/25/accepted PY - 2016/3/19/entrez PY - 2016/3/19/pubmed PY - 2016/8/4/medline SP - e1005942 EP - e1005942 JF - PLoS genetics JO - PLoS Genet VL - 12 IS - 3 N2 - Because DNA double-strand breaks (DSBs) are one of the most cytotoxic DNA lesions and often cause genomic instability, precise repair of DSBs is vital for the maintenance of genomic stability. Xrs2/Nbs1 is a multi-functional regulatory subunit of the Mre11-Rad50-Xrs2/Nbs1 (MRX/N) complex, and its function is critical for the primary step of DSB repair, whether by homologous recombination (HR) or non-homologous end joining. In human NBS1, mutations result truncation of the N-terminus region, which contains a forkhead-associated (FHA) domain, cause Nijmegen breakage syndrome. Here we show that the Xrs2 FHA domain of budding yeast is required both to suppress the imprecise repair of DSBs and to promote the robust activation of Tel1 in the DNA damage response pathway. The role of the Xrs2 FHA domain in Tel1 activation was independent of the Tel1-binding activity of the Xrs2 C terminus, which mediates Tel1 recruitment to DSB ends. Both the Xrs2 FHA domain and Tel1 were required for the timely removal of the Ku complex from DSB ends, which correlates with a reduced frequency of imprecise end-joining. Thus, the Xrs2 FHA domain and Tel1 kinase work in a coordinated manner to maintain DSB repair fidelity. SN - 1553-7404 UR - https://www.unboundmedicine.com/medline/citation/26990569/The_MRX_Complex_Ensures_NHEJ_Fidelity_through_Multiple_Pathways_Including_Xrs2_FHA_Dependent_Tel1_Activation_ L2 - https://dx.plos.org/10.1371/journal.pgen.1005942 DB - PRIME DP - Unbound Medicine ER -