Mitotic single-stranded DNA suppression by DDIAS.

Cells undergoing division mount a unique response to DNA damage that ensures accurate chromosome segregation. The CIP2A-TOPBP1 complex has emerged as an important mitotic genome maintenance factor, but its function remains unclear. Here, we report that DDIAS is a DNA-binding effector of the CIP2A pathway in human cells. DDIAS physically interacts with TOPBP1, and its inactivation causes synthetic lethality with BRCA1 and BRCA2 deficiency. Homologous recombination (HR)-deficient tumors upregulate DDIAS to enable HR-deficient cells to tolerate their genomic instability. Mechanistically, DDIAS is a single-stranded DNA (ssDNA)-binding protein that promotes the repair of ssDNA carried from interphase into mitosis. Mitotic ssDNA in HR-deficient cells is exacerbated by poly(ADP-ribose) polymerase (PARP) inhibition, and DDIAS-dependent suppression of these lesions involves mitotic DNA synthesis, which promotes accurate chromosome segregation and survival. We propose that DDIAS defines a mitotic DNA repair system downstream of CIP2A that mitigates the threat of mitotic ssDNA for genome integrity.