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Sae2 promotes DNA damage resistance by removing the Mre11-Rad50-Xrs2 complex from DNA and attenuating Rad53 signaling.
Proc Natl Acad Sci U S A. 2015 Apr 14; 112(15):E1880-7.PN

Abstract

The Mre11-Rad50-Xrs2/NBS1 (MRX/N) nuclease/ATPase complex plays structural and catalytic roles in the repair of DNA double-strand breaks (DSBs) and is the DNA damage sensor for Tel1/ATM kinase activation. Saccharomyces cerevisiae Sae2 can function with MRX to initiate 5'-3' end resection and also plays an important role in attenuation of DNA damage signaling. Here we describe a class of mre11 alleles that suppresses the DNA damage sensitivity of sae2Δ cells by accelerating turnover of Mre11 at DNA ends, shutting off the DNA damage checkpoint and allowing cell cycle progression. The mre11 alleles do not suppress the end resection or hairpin-opening defects of the sae2Δ mutant, indicating that these functions of Sae2 are not responsible for DNA damage resistance. The purified M(P110L)RX complex shows reduced binding to single- and double-stranded DNA in vitro relative to wild-type MRX, consistent with the increased turnover of Mre11 from damaged sites in vivo. Furthermore, overproduction of Mre11 causes DNA damage sensitivity only in the absence of Sae2. Together, these data suggest that it is the failure to remove Mre11 from DNA ends and attenuate Rad53 kinase signaling that causes hypersensitivity of sae2Δ cells to clastogens.

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Authors+Show Affiliations

Chen H
Department of Microbiology & Immunology, Columbia University Medical Center, New York, NY 10032; Department of Biological Sciences, Columbia University, New York, NY 10016; and.
Donnianni RA
Department of Microbiology & Immunology, Columbia University Medical Center, New York, NY 10032;
Handa N
Department of Microbiology & Molecular Genetics and Department of Molecular and Cellular Biology, University of California, Davis, CA 95616.
Deng SK
Department of Microbiology & Immunology, Columbia University Medical Center, New York, NY 10032;
Oh J
Department of Microbiology & Immunology, Columbia University Medical Center, New York, NY 10032; Department of Biological Sciences, Columbia University, New York, NY 10016; and.
Timashev LA
Department of Microbiology & Immunology, Columbia University Medical Center, New York, NY 10032;
Kowalczykowski SC
Department of Microbiology & Molecular Genetics and Department of Molecular and Cellular Biology, University of California, Davis, CA 95616 lss5@columbia.edu sckowalczykowski@ucdavis.edu.
Symington LS
Department of Microbiology & Immunology, Columbia University Medical Center, New York, NY 10032; lss5@columbia.edu sckowalczykowski@ucdavis.edu.

MeSH

Cell CycleCell Cycle ProteinsCheckpoint Kinase 2DNA Breaks, Double-StrandedDNA DamageDNA RepairDNA, FungalDNA-Binding ProteinsEndodeoxyribonucleasesEndonucleasesExodeoxyribonucleasesMicroscopy, FluorescenceMultiprotein ComplexesMutationProtein BindingSaccharomyces cerevisiae ProteinsSignal Transduction

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25831494

Citation

Chen, Huan, et al. "Sae2 Promotes DNA Damage Resistance By Removing the Mre11-Rad50-Xrs2 Complex From DNA and Attenuating Rad53 Signaling." Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 15, 2015, pp. E1880-7.
Chen H, Donnianni RA, Handa N, et al. Sae2 promotes DNA damage resistance by removing the Mre11-Rad50-Xrs2 complex from DNA and attenuating Rad53 signaling. Proc Natl Acad Sci U S A. 2015;112(15):E1880-7.
Chen, H., Donnianni, R. A., Handa, N., Deng, S. K., Oh, J., Timashev, L. A., Kowalczykowski, S. C., & Symington, L. S. (2015). Sae2 promotes DNA damage resistance by removing the Mre11-Rad50-Xrs2 complex from DNA and attenuating Rad53 signaling. Proceedings of the National Academy of Sciences of the United States of America, 112(15), E1880-7. https://doi.org/10.1073/pnas.1503331112
Chen H, et al. Sae2 Promotes DNA Damage Resistance By Removing the Mre11-Rad50-Xrs2 Complex From DNA and Attenuating Rad53 Signaling. Proc Natl Acad Sci U S A. 2015 Apr 14;112(15):E1880-7. PubMed PMID: 25831494.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Sae2 promotes DNA damage resistance by removing the Mre11-Rad50-Xrs2 complex from DNA and attenuating Rad53 signaling. AU - Chen,Huan, AU - Donnianni,Roberto A, AU - Handa,Naofumi, AU - Deng,Sarah K, AU - Oh,Julyun, AU - Timashev,Leonid A, AU - Kowalczykowski,Stephen C, AU - Symington,Lorraine S, Y1 - 2015/03/23/ PY - 2015/4/2/entrez PY - 2015/4/2/pubmed PY - 2015/7/25/medline KW - DNA damage checkpoint KW - DNA repair KW - Mre11 KW - Sae2 SP - E1880 EP - 7 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc Natl Acad Sci U S A VL - 112 IS - 15 N2 - The Mre11-Rad50-Xrs2/NBS1 (MRX/N) nuclease/ATPase complex plays structural and catalytic roles in the repair of DNA double-strand breaks (DSBs) and is the DNA damage sensor for Tel1/ATM kinase activation. Saccharomyces cerevisiae Sae2 can function with MRX to initiate 5'-3' end resection and also plays an important role in attenuation of DNA damage signaling. Here we describe a class of mre11 alleles that suppresses the DNA damage sensitivity of sae2Δ cells by accelerating turnover of Mre11 at DNA ends, shutting off the DNA damage checkpoint and allowing cell cycle progression. The mre11 alleles do not suppress the end resection or hairpin-opening defects of the sae2Δ mutant, indicating that these functions of Sae2 are not responsible for DNA damage resistance. The purified M(P110L)RX complex shows reduced binding to single- and double-stranded DNA in vitro relative to wild-type MRX, consistent with the increased turnover of Mre11 from damaged sites in vivo. Furthermore, overproduction of Mre11 causes DNA damage sensitivity only in the absence of Sae2. Together, these data suggest that it is the failure to remove Mre11 from DNA ends and attenuate Rad53 kinase signaling that causes hypersensitivity of sae2Δ cells to clastogens. SN - 1091-6490 UR - https://www.unboundmedicine.com/medline/citation/25831494/Sae2_promotes_DNA_damage_resistance_by_removing_the_Mre11_Rad50_Xrs2_complex_from_DNA_and_attenuating_Rad53_signaling_ DB - PRIME DP - Unbound Medicine ER -