Rad9/53BP1 promotes DNA repair via crossover recombination by limiting the Sgs1 and Mph1 helicases

Matteo Ferrari; Chetan C Rawal; Samuele Lodovichi; Maria Y Vietri; Achille Pellicioli

doi:10.1038/s41467-020-16997-w

Rad9/53BP1 promotes DNA repair via crossover recombination by limiting the Sgs1 and Mph1 helicases

Nat Commun. 2020 Jun 23;11(1):3181. doi: 10.1038/s41467-020-16997-w.

Authors

Matteo Ferrari^{1

2}, Chetan C Rawal^{1

3}, Samuele Lodovichi¹, Maria Y Vietri¹, Achille Pellicioli⁴

Affiliations

¹ Dipartimento di Bioscienze, Università degli Studi di Milano, Via Celoria 26, 20131, Milano, Italia.
² Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
³ Department of Molecular and Computational Biology, University of Southern California, Los Angeles, CA, 90089, USA.
⁴ Dipartimento di Bioscienze, Università degli Studi di Milano, Via Celoria 26, 20131, Milano, Italia. achille.pellicioli@unimi.it.

Abstract

The DNA damage checkpoint (DDC) is often robustly activated during the homologous recombination (HR) repair of DNA double strand breaks (DSBs). DDC activation controls several HR repair factors by phosphorylation, preventing premature segregation of entangled chromosomes formed during HR repair. The DDC mediator 53BP1/Rad9 limits the nucleolytic processing (resection) of a DSB, controlling the formation of the 3' single-stranded DNA (ssDNA) filament needed for recombination, from yeast to human. Here we show that Rad9 promotes stable annealing between the recombinogenic filament and the donor template in yeast, limiting strand rejection by the Sgs1 and Mph1 helicases. This regulation allows repair by long tract gene conversion, crossover recombination and break-induced replication (BIR), only after DDC activation. These findings shed light on how cells couple DDC with the choice and effectiveness of HR sub-pathways, with implications for genome instability and cancer.

Publication types

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

MeSH terms

Cell Cycle Proteins / genetics
Cell Cycle Proteins / metabolism*
Cell Survival
DEAD-box RNA Helicases / metabolism
DNA Breaks, Double-Stranded
DNA Repair / genetics*
DNA Repair / physiology*
DNA, Single-Stranded
DNA-Binding Proteins / metabolism
Gene Conversion
Genomic Instability
Homologous Recombination
Humans
Rad52 DNA Repair and Recombination Protein / metabolism
RecQ Helicases / metabolism
Recombinational DNA Repair
Saccharomyces cerevisiae / genetics*
Saccharomyces cerevisiae / metabolism*
Saccharomyces cerevisiae Proteins / genetics
Saccharomyces cerevisiae Proteins / metabolism*
Tumor Suppressor p53-Binding Protein 1 / genetics
Tumor Suppressor p53-Binding Protein 1 / metabolism*

Substances

Cell Cycle Proteins
DNA, Single-Stranded
DNA-Binding Proteins
Rad52 DNA Repair and Recombination Protein
Saccharomyces cerevisiae Proteins
TP53BP1 protein, human
Tumor Suppressor p53-Binding Protein 1
rad9 protein
MPH1 protein, S cerevisiae
SGS1 protein, S cerevisiae
RecQ Helicases
DEAD-box RNA Helicases