The MRX complex stabilizes the replisome independently of the S phase checkpoint during replication stress.
The Mre11-Rad50-Xrs2 (MRX) complex has an important function in the maintenance of genomic integrity by contributing to the detection and repair of chromosome breaks. Here we show that the complex is recruited to sites of paused forks where it stabilizes the association of essential replisome components. Interestingly, this function is not dependent on the S phase checkpoint or the nuclease activity of Mre11. We find that disruption of the MRX complex leads to a loss of fork recovery and a failure to properly complete DNA replication when cells are exposed to replication stress. Our data suggest that one critical function of the MRX complex during replication is to promote the cohesion of sister chromatids at paused forks, offering an explanation for why MRX deficiency leads to a loss of cell viability and high levels of chromosome rearrangements under conditions of replication stress.
Tittel-Elmer
Mireille
M
Department of Biochemistry and Molecular Biology, Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada.
Alabert
Constance
C
Pasero
Philippe
P
Cobb
Jennifer A
JA
D000818:Animals; D004257:DNA Polymerase II / Q000378:metabolism; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004706:Endodeoxyribonucleases / Q000235:genetics / Q000378:metabolism*; D004843:Epistasis, Genetic; D005090:Exodeoxyribonucleases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006918:Hydroxyurea / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism*; D011500:Protein Synthesis Inhibitors / Q000378:metabolism; D016196:S Phase / Q000502:physiology*; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; D046912:Multiprotein Complexes; D011500:Protein Synthesis Inhibitors; C086930:RAD50 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C086929:XRS2 protein, S cerevisiae; D004257:DNA Polymerase II; D004706:Endodeoxyribonucleases; D005090:Exodeoxyribonucleases; C094191:MRE11 protein, S cerevisiae; D006918:Hydroxyurea