DDIAS shields single-stranded DNA in mitosis and promotes vertebrate brain development.

DNA double-strand breaks and unresolved DNA replication intermediates are particularly dangerous during mitosis. Paradoxically, cells inactivate canonical DNA repair mechanisms during chromosome segregation in favor of alternative pathways that depend on TOPBP1 and CIP2A, but how these pathways function is still poorly defined. Here, we describe the identification of DDIAS as a mitosis-specific DNA damage response protein. We establish DDIAS as a phosphorylation-dependent component and effector of the TOPBP1-CIP2A complex, and we demonstrate that DDIAS protects single-stranded DNA from aberrant nucleolytic processing to safeguard chromosome integrity during mitosis, particularly in BRCA1-/BRCA2-deficient cells. We also identify biallelic inactivating mutations in DDIAS in patients with a severe neurodevelopmental disorder and, using human cerebral organoids and zebrafish, we show that DDIAS plays a critical and evolutionarily conserved role in limiting DNA damage specifically in neural progenitor cells. These findings demonstrate a physiological role for the DNA damage response in mitosis during vertebrate neurodevelopment.