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Functional interplay between the 53BP1-ortholog Rad9 and the Mre11 complex regulates resection, end-tethering and repair of a double-strand break.
PLoS Genet. 2015 Jan; 11(1):e1004928.PG

Abstract

The Mre11-Rad50-Xrs2 nuclease complex, together with Sae2, initiates the 5'-to-3' resection of Double-Strand DNA Breaks (DSBs). Extended 3' single stranded DNA filaments can be exposed from a DSB through the redundant activities of the Exo1 nuclease and the Dna2 nuclease with the Sgs1 helicase. In the absence of Sae2, Mre11 binding to a DSB is prolonged, the two DNA ends cannot be kept tethered, and the DSB is not efficiently repaired. Here we show that deletion of the yeast 53BP1-ortholog RAD9 reduces Mre11 binding to a DSB, leading to Rad52 recruitment and efficient DSB end-tethering, through an Sgs1-dependent mechanism. As a consequence, deletion of RAD9 restores DSB repair either in absence of Sae2 or in presence of a nuclease defective MRX complex. We propose that, in cells lacking Sae2, Rad9/53BP1 contributes to keep Mre11 bound to a persistent DSB, protecting it from extensive DNA end resection, which may lead to potentially deleterious DNA deletions and genome rearrangements.

Authors+Show Affiliations

Department of Biosciences, University of Milan, Milano, Italy.Department of Biosciences, University of Milan, Milano, Italy.Department of Biosciences, University of Milan, Milano, Italy.Department of Biology and Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, Massachusetts, United States of America.Department of Biosciences, University of Milan, Milano, Italy.Department of Biosciences, University of Milan, Milano, Italy.Department of Biology and Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, Massachusetts, United States of America.Department of Biosciences, University of Milan, Milano, Italy.Department of Biology and Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, Massachusetts, United States of America.Department of Biosciences, University of Milan, Milano, Italy.

Pub Type(s)

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

Language

eng

PubMed ID

25569305

Citation

Ferrari, Matteo, et al. "Functional Interplay Between the 53BP1-ortholog Rad9 and the Mre11 Complex Regulates Resection, End-tethering and Repair of a Double-strand Break." PLoS Genetics, vol. 11, no. 1, 2015, pp. e1004928.
Ferrari M, Dibitetto D, De Gregorio G, et al. Functional interplay between the 53BP1-ortholog Rad9 and the Mre11 complex regulates resection, end-tethering and repair of a double-strand break. PLoS Genet. 2015;11(1):e1004928.
Ferrari, M., Dibitetto, D., De Gregorio, G., Eapen, V. V., Rawal, C. C., Lazzaro, F., Tsabar, M., Marini, F., Haber, J. E., & Pellicioli, A. (2015). Functional interplay between the 53BP1-ortholog Rad9 and the Mre11 complex regulates resection, end-tethering and repair of a double-strand break. PLoS Genetics, 11(1), e1004928. https://doi.org/10.1371/journal.pgen.1004928
Ferrari M, et al. Functional Interplay Between the 53BP1-ortholog Rad9 and the Mre11 Complex Regulates Resection, End-tethering and Repair of a Double-strand Break. PLoS Genet. 2015;11(1):e1004928. PubMed PMID: 25569305.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Functional interplay between the 53BP1-ortholog Rad9 and the Mre11 complex regulates resection, end-tethering and repair of a double-strand break. AU - Ferrari,Matteo, AU - Dibitetto,Diego, AU - De Gregorio,Giuseppe, AU - Eapen,Vinay V, AU - Rawal,Chetan C, AU - Lazzaro,Federico, AU - Tsabar,Michael, AU - Marini,Federica, AU - Haber,James E, AU - Pellicioli,Achille, Y1 - 2015/01/08/ PY - 2014/06/27/received PY - 2014/11/30/accepted PY - 2015/1/9/entrez PY - 2015/1/9/pubmed PY - 2015/7/1/medline SP - e1004928 EP - e1004928 JF - PLoS genetics JO - PLoS Genet VL - 11 IS - 1 N2 - The Mre11-Rad50-Xrs2 nuclease complex, together with Sae2, initiates the 5'-to-3' resection of Double-Strand DNA Breaks (DSBs). Extended 3' single stranded DNA filaments can be exposed from a DSB through the redundant activities of the Exo1 nuclease and the Dna2 nuclease with the Sgs1 helicase. In the absence of Sae2, Mre11 binding to a DSB is prolonged, the two DNA ends cannot be kept tethered, and the DSB is not efficiently repaired. Here we show that deletion of the yeast 53BP1-ortholog RAD9 reduces Mre11 binding to a DSB, leading to Rad52 recruitment and efficient DSB end-tethering, through an Sgs1-dependent mechanism. As a consequence, deletion of RAD9 restores DSB repair either in absence of Sae2 or in presence of a nuclease defective MRX complex. We propose that, in cells lacking Sae2, Rad9/53BP1 contributes to keep Mre11 bound to a persistent DSB, protecting it from extensive DNA end resection, which may lead to potentially deleterious DNA deletions and genome rearrangements. SN - 1553-7404 UR - https://www.unboundmedicine.com/medline/citation/25569305/Functional_interplay_between_the_53BP1_ortholog_Rad9_and_the_Mre11_complex_regulates_resection_end_tethering_and_repair_of_a_double_strand_break_ L2 - https://dx.plos.org/10.1371/journal.pgen.1004928 DB - PRIME DP - Unbound Medicine ER -