SMAD4 loss drives cancer chromosomal instability through transcription-replication conflict-induced replication stress

Abstract

Cancer chromosomal instability (CIN) drives tumor evolution through generating structural and numerical chromosome aberrations. However, its molecular determinants remain poorly characterized. Here, we uncover a yet unrecognized role for the tumor suppressor SMAD4 as a key regulator of genome stability. Mechanistically, loss of SMAD4 induces replication stress by promoting transcription-replication conflicts (TRCs), which induces chromosomal breaks and subsequent mitotic errors, leading to the concomitant emergence of structural and numerical CIN. While the tumor suppressor function of SMAD4 has been predominantly attributed to TGF-{beta} signaling, we find that its role in genome maintenance operates via BMP signaling and its transcriptional target gene ID3. Consequently, inhibition of BMP signaling mimics the loss of SMAD4 whereas re-expression of SMAD4 or ID3 suppresses TRCs, replication stress and mitotic errors in SMAD4-deficient cancer cells. Our findings reveal a TRC- and replication stress-driven mechanism by which loss of BMP-SMAD4 signaling causes cancer chromosomal instability.