Genetic Interaction Landscape Reveals Critical Requirements for Schizosaccharomyces pombe Brc1 in DNA Damage Response Mutants

G3 : Genes - Genomes - Genetics
Arancha SánchezPaul Russell

Abstract

Brc1, which was first identified as a high-copy, allele-specific suppressor of a mutation impairing the Smc5-Smc6 holocomplex in Schizosaccharomyces pombe, protects genome integrity during normal DNA replication and when cells are exposed to toxic compounds that stall or collapse replication forks. The C-terminal tandem BRCT (BRCA1 C-terminus) domain of fission yeast Brc1 docks with phosphorylated histone H2A (γH2A)-marked chromatin formed by ATR/Rad3 checkpoint kinase at arrested and damaged replication forks; however, how Brc1 functions in relation to other genome protection modules remains unclear. Here, an epistatic mini-array profile reveals critical requirements for Brc1 in mutants that are defective in multiple DNA damage response pathways, including checkpoint signaling by Rad3-Rad26/ATR-ATRIP kinase, DNA repair by Smc5-Smc6 holocomplex, replication fork stabilization by Mrc1/claspin and Swi1-Swi3/Timeless-Tipin, and control of ubiquitin-regulated proteolysis by the COP9 signalosome (CSN). Exogenous genotoxins enhance these negative genetic interactions. Rad52 and RPA foci are increased in CSN-defective cells, and loss of γH2A increases genotoxin sensitivity, indicating a critical role for the γH2A-Brc1 module in stabil...Continue Reading

References

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Citations

Nov 3, 2015·Critical Reviews in Biochemistry and Molecular Biology·Charalampos Rallis, Jürg Bähler
Oct 18, 2016·Cell Cycle·Bingbing WanXiaolan Zhao
Aug 9, 2017·Molecular and Cellular Biology·Michael C ReubensPaul Russell
Oct 24, 2018·Molecular and Cellular Biology·Martina OravcováMichael N Boddy
Jan 3, 2019·Current Genetics·Martina Oravcová, Michael N Boddy

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