Tel1 and Rif2 Regulate MRX Functions in End-Tethering and Repair of DNA Double-Strand Breaks

PLoS Biology
Corinne CassaniMaria Pia Longhese

Abstract

The cellular response to DNA double-strand breaks (DSBs) is initiated by the MRX/MRN complex (Mre11-Rad50-Xrs2 in yeast; Mre11-Rad50-Nbs1 in mammals), which recruits the checkpoint kinase Tel1/ATM to DSBs. In Saccharomyces cerevisiae, the role of Tel1 at DSBs remains enigmatic, as tel1Δ cells do not show obvious hypersensitivity to DSB-inducing agents. By performing a synthetic phenotype screen, we isolated a rad50-V1269M allele that sensitizes tel1Δ cells to genotoxic agents. The MRV1269MX complex associates poorly to DNA ends, and its retention at DSBs is further reduced by the lack of Tel1. As a consequence, tel1Δ rad50-V1269M cells are severely defective both in keeping the DSB ends tethered to each other and in repairing a DSB by either homologous recombination (HR) or nonhomologous end joining (NHEJ). These data indicate that Tel1 promotes MRX retention to DSBs and this function is important to allow proper MRX-DNA binding that is needed for end-tethering and DSB repair. The role of Tel1 in promoting MRX accumulation to DSBs is counteracted by Rif2, which is recruited to DSBs. We also found that Rif2 enhances ATP hydrolysis by MRX and attenuates MRX function in end-tethering, suggesting that Rif2 can regulate MRX activity...Continue Reading

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Citations

May 5, 2016·Cellular and Molecular Life Sciences : CMLS·Matteo VillaMaria Pia Longhese
Aug 9, 2016·Progress in Biophysics and Molecular Biology·Logan R Myler, Ilya J Finkelstein
Jan 31, 2019·Nucleic Acids Research·Corinne CassaniMaria Pia Longhese
Jun 22, 2018·The EMBO Journal·Elisa GobbiniMaria Pia Longhese
Dec 13, 2018·Genetics·Chiara Vittoria ColomboMaria Pia Longhese
Oct 24, 2019·The Journal of Biological Chemistry·Sarem HailemariamPeter M Burgers
Sep 28, 2018·Frontiers in Genetics·Diego BonettiMaria Pia Longhese
Jun 25, 2019·Frontiers in Molecular Biosciences·Erika CasariMaria Pia Longhese
Mar 29, 2020·Biochemical Society Transactions·Chiara Vittoria ColomboMaria Pia Longhese
Dec 7, 2018·Genes·Julyun Oh, Lorraine S Symington
Mar 27, 2021·Biochemical Society Transactions·Michela GalliMichela Clerici
May 14, 2021·Nature Communications·Florian Roisné-HamelinStéphane Marcand
Jun 22, 2021·Critical Reviews in Biochemistry and Molecular Biology·Elias A Tannous, Peter M Burgers
Jun 24, 2021·Nature Communications·Freddy KhayatAlessandro Bianchi
Jul 27, 2021·Current Opinion in Genetics & Development·Diego BonettiMaria Pia Longhese
Nov 24, 2021·Annual Review of Genetics·Petr Cejka, Lorraine S Symington
Jan 20, 2022·ELife·Fernando Rodrigo Rosas BringasMichael Chang

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Methods Mentioned

BETA
gel filtration
immunoprecipitation
PCR
ChIP
FACS
dissection
in vitro transcription
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