Here, we show that deficiency of the essential replisome component Mcm10 dramatically elevates (GAA)n repeat instability in a budding yeast model by loss of proper CMG helicase interaction. When repair is inefficient, such as in the case of RPA depletion, breakage of under-replicated repetitive DNA can occur during G2/M, leading to loss of essential genes and cell death. We hypothesize that the CMG-Mcm10 interaction promotes replication through hard-to-replicate regions, assuring genome stability and cell survival.