The replication stress response suppresses mutation rates in mismatch repair deficient budding yeast and human cancers

Abstract

Elevated mutation rate is a hallmark of mismatch repair (MMR) deficient cells and tumours. This includes microsatellite instability (MSI), which is caused by insertions and deletions in mono-and dinucleotide repeats. MSI rates, however, are highly variable across MMR-deficient tumours. Here we show that mutation rates are genetically regulated in MMR-deficient cells. A genome-wide deletion screen in budding yeast revealed that 3% gene deletions caused mutation rates to be further elevated, whereas 11% reduced mutation rates. The genes causing an elevation are enriched for DNA repair and replication processes, whereas deletion of genes implicated in transcriptional processes reduce mutation rates. A pan-cancer analysis of MSI revealed that mutations in replication stress response (ATR, TOPBP1, CHEK1) or DNA repair genes (RAD50, TOP3A) was associated with extreme rates of MSI in MMR-defective tumours, but not when mutated on their own. Since replication stress, DNA damage and repair activities are cell-type specific, this may account for highly variable mutation rates associated with different MMR-deficient tumours.