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Sae2 antagonizes Rad9 accumulation at DNA double-strand breaks to attenuate checkpoint signaling and facilitate end resection.
Proc Natl Acad Sci U S A. 2018 12 18; 115(51):E11961-E11969.PN

Abstract

The Mre11-Rad50-Xrs2NBS1 complex plays important roles in the DNA damage response by activating the Tel1ATM kinase and catalyzing 5'-3' resection at DNA double-strand breaks (DSBs). To initiate resection, Mre11 endonuclease nicks the 5' strands at DSB ends in a reaction stimulated by Sae2CtIP Accordingly, Mre11-nuclease deficient (mre11-nd) and sae2Δ mutants are expected to exhibit similar phenotypes; however, we found several notable differences. First, sae2Δ cells exhibit greater sensitivity to genotoxins than mre11-nd cells. Second, sae2Δ is synthetic lethal with sgs1Δ, whereas the mre11-nd sgs1Δ mutant is viable. Third, Sae2 attenuates the Tel1-Rad53CHK2 checkpoint and antagonizes Rad953BP1 accumulation at DSBs independent of Mre11 nuclease. We show that Sae2 competes with other Tel1 substrates, thus reducing Rad9 binding to chromatin and to Rad53. We suggest that persistent Sae2 binding at DSBs in the mre11-nd mutant counteracts the inhibitory effects of Rad9 and Rad53 on Exo1 and Dna2-Sgs1-mediated resection, accounting for the different phenotypes conferred by mre11-nd and sae2Δ mutations. Collectively, these data show a resection initiation independent role for Sae2 at DSBs by modulating the DNA damage checkpoint.

Authors+Show Affiliations

Department of Microbiology & Immunology, Columbia University Irving Medical Center, New York, NY 10032.Department of Microbiology & Immunology, Columbia University Irving Medical Center, New York, NY 10032. Program in Biological Sciences, Columbia University, New York, NY 10027.Department of Microbiology & Immunology, Columbia University Irving Medical Center, New York, NY 10032; lss5@cumc.columbia.edu. Program in Biological Sciences, Columbia University, New York, NY 10027.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

30510002

Citation

Yu, Tai-Yuan, et al. "Sae2 Antagonizes Rad9 Accumulation at DNA Double-strand Breaks to Attenuate Checkpoint Signaling and Facilitate End Resection." Proceedings of the National Academy of Sciences of the United States of America, vol. 115, no. 51, 2018, pp. E11961-E11969.
Yu TY, Kimble MT, Symington LS. Sae2 antagonizes Rad9 accumulation at DNA double-strand breaks to attenuate checkpoint signaling and facilitate end resection. Proc Natl Acad Sci U S A. 2018;115(51):E11961-E11969.
Yu, T. Y., Kimble, M. T., & Symington, L. S. (2018). Sae2 antagonizes Rad9 accumulation at DNA double-strand breaks to attenuate checkpoint signaling and facilitate end resection. Proceedings of the National Academy of Sciences of the United States of America, 115(51), E11961-E11969. https://doi.org/10.1073/pnas.1816539115
Yu TY, Kimble MT, Symington LS. Sae2 Antagonizes Rad9 Accumulation at DNA Double-strand Breaks to Attenuate Checkpoint Signaling and Facilitate End Resection. Proc Natl Acad Sci U S A. 2018 12 18;115(51):E11961-E11969. PubMed PMID: 30510002.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Sae2 antagonizes Rad9 accumulation at DNA double-strand breaks to attenuate checkpoint signaling and facilitate end resection. AU - Yu,Tai-Yuan, AU - Kimble,Michael T, AU - Symington,Lorraine S, Y1 - 2018/12/03/ PY - 2018/12/5/pubmed PY - 2019/2/16/medline PY - 2018/12/5/entrez KW - DNA damage checkpoint KW - DNA repair KW - Mre11 KW - Rad9 KW - Sae2 SP - E11961 EP - E11969 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc Natl Acad Sci U S A VL - 115 IS - 51 N2 - The Mre11-Rad50-Xrs2NBS1 complex plays important roles in the DNA damage response by activating the Tel1ATM kinase and catalyzing 5'-3' resection at DNA double-strand breaks (DSBs). To initiate resection, Mre11 endonuclease nicks the 5' strands at DSB ends in a reaction stimulated by Sae2CtIP Accordingly, Mre11-nuclease deficient (mre11-nd) and sae2Δ mutants are expected to exhibit similar phenotypes; however, we found several notable differences. First, sae2Δ cells exhibit greater sensitivity to genotoxins than mre11-nd cells. Second, sae2Δ is synthetic lethal with sgs1Δ, whereas the mre11-nd sgs1Δ mutant is viable. Third, Sae2 attenuates the Tel1-Rad53CHK2 checkpoint and antagonizes Rad953BP1 accumulation at DSBs independent of Mre11 nuclease. We show that Sae2 competes with other Tel1 substrates, thus reducing Rad9 binding to chromatin and to Rad53. We suggest that persistent Sae2 binding at DSBs in the mre11-nd mutant counteracts the inhibitory effects of Rad9 and Rad53 on Exo1 and Dna2-Sgs1-mediated resection, accounting for the different phenotypes conferred by mre11-nd and sae2Δ mutations. Collectively, these data show a resection initiation independent role for Sae2 at DSBs by modulating the DNA damage checkpoint. SN - 1091-6490 UR - https://www.unboundmedicine.com/medline/citation/30510002/Sae2_antagonizes_Rad9_accumulation_at_DNA_double_strand_breaks_to_attenuate_checkpoint_signaling_and_facilitate_end_resection_ L2 - http://www.pnas.org/cgi/pmidlookup?view=long&pmid=30510002 DB - PRIME DP - Unbound Medicine ER -