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

DDIAS, a phosphorylation-dependent effector of the TOPBP1-CIP2A complex, protects single-stranded DNA from aberrant nucleolytic processing during mitosis; biallelic inactivating mutations are reported in patients with a severe neurodevelopmental disorder.

DNA double-strand breaks and unresolved replication intermediates are especially dangerous during mitosis, when cells switch off canonical repair pathways in favour of pathways that depend on TOPBP1 and CIP2A. The authors identify DDIAS as a mitosis-specific DNA damage response protein and a phosphorylation-dependent component and effector of the TOPBP1-CIP2A complex, showing that it protects single-stranded DNA from aberrant nucleolytic processing and safeguards chromosome integrity, particularly in BRCA1- and BRCA2-deficient cells. They also report biallelic inactivating mutations in DDIAS in patients with a severe neurodevelopmental disorder. Using human cerebral organoids and zebrafish, they show that DDIAS has a critical, evolutionarily conserved role in limiting DNA damage specifically in neural progenitor cells.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The mechanistic work is solid, but the human component amounts to a single statement that biallelic inactivating mutations were found in patients: the abstract gives no case count, no phenotypic description and no variant details, so the strength of the gene-disease association cannot be judged. That is enough to put DDIAS on the list when biallelic variants appear in a severe neurodevelopmental disorder, yet interpreting an isolated DDIAS variant will remain difficult until the phenotypic spectrum and the number of cases are published. The link with BRCA1 or BRCA2 deficiency belongs to cancer biology for now, with no immediate clinical translation.

Analysis by Dr Thibaut Benquey