Loss-of-function mutations in genome maintenance genes fuel tumorigenesis through increased genomic instability. A subset of these tumor suppressors are challenging to identify due to context dependency, including functional interactions with other genes and pathways. Here, we searched for potential causal genes that impact tumor development and/or progression in breast cancer through functional-genetic screening of candidate genes. MYH4, encoding a class II myosin, emerged as a top hit impacting genomic stability. We show that MYH4 suppresses DNA replication stress by promoting replication licensing and replication fork progression. Moreover, we observed a strong synergistic relationship among class II myosins in suppressing replication-associated DNA damage. Genomic analysis of Pan-Cancer Analysis of Whole Genomes project breast cancer samples revealed frequent concomitant loss of TP53 with MYH4 and class II myosins on chromosome 17p. Notably, Myh4 disruption accelerated mouse mammary tumorigenesis in a Trp53-deficient background. In conclusion, our results suggest an unanticipated function of MYH4 in p53-mediated tumor suppression that can explain their combined loss in breast cancer.
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