The tumor suppressor SMAD4 is a gatekeeper for genome stability

Cancer chromosomal instability (CIN) causes structural and numerical chromosome aberrations and acts as a driver for tumor progression and poor patient outcome. However, the mechanisms driving CIN are incompletely understood. In this study, we identified SMAD4, a key tumor suppressor in colorectal and pancreatic cancers, as a gatekeeper for genome stability. Loss of SMAD4 results in homologous recombination DNA repair defects, DNA replication stress and mitotic errors, resulting in genome instability. SMAD4 acts as part of BMP signaling and ensures genome stability through its transcriptional target inhibitor of DNA binding 3 (ID3). Consequently, abrogation of BMP signaling or ID3 phenocopies the genome maintenance defects induced upon loss of SMAD4. Thus, our study defines SMAD4 as a key suppressor of genome instability in human cancer.