Maintaining genome stability is critical for normal cell function, with extensive DNA damage response networks in place to detect and repair DNA lesions. However, during mitosis, most DNA repair pathways and damage checkpoints are inactivated. Previous studies have identified a mitosis-specific DNA damage response centred on the TOPBP1–CIP2A complex, but how this protects damaged DNA has remained poorly understood.
The new findings establish DDIAS as a third core component of this complex and provide the first link between disruption of this mitotic DNA protection pathway and human genetic disease.
The discovery began with the identification of a biallelic inactivating mutation in the DDIAS gene in two individuals presenting with clinical features characteristic of chromosome instability syndromes, including microcephaly, developmental delay and intellectual disability. This led an international team of researchers from the UK, Denmark, Pakistan and Norway to investigate the role of DDIAS in the DNA damage response.
Patient-derived cells exposed to genotoxic agents showed increased chromosome abnormalities and micronuclei, a marker of chromosome instability. Reintroducing normal DDIAS into the cells reduced these abnormalities to baseline levels, demonstrating a direct role for DDIAS in maintaining chromosome integrity.
The researchers then examined how DDIAS responds to DNA damage. During interphase, DDIAS was distributed throughout the nucleus. In cells undergoing mitosis, however, it accumulated at sites marked by γH2AX, a marker of DNA damage. Recruitment of DDIAS to these sites depended on TOPBP1 and CIP2A, placing DDIAS downstream of the established TOPBP1–CIP2A complex. They also found that DDIAS binds single-stranded DNA (ssDNA), which can arise at sites of incomplete DNA replication or damage.
Dr Andrew Blackford said:
“Our finding that DDIAS loss in patients results in features of a chromosome instability syndrome led us to investigate the role of this poorly understood protein in the DNA damage response. Our work suggests a model in which DDIAS is the third core component of the mitotic TOPBP1-CIP2A complex, acting to safeguard chromosome integrity during cell division through its ability to bind single-stranded DNA.”
The team wanted to understand the mechanisms through which DDIAS binding to ssDNA maintained genome stability. DDIAS did not appear to promote mitotic DNA synthesis, DNA end tethering or DNA double-strand break repair during mitosis. Instead, the findings indicate that DDIAS protects exposed ssDNA from aberrant enzymatic processing, including toxic processing by the nuclease DNA2.
© Tsukada, et al. 2026. Reproduced from Cell [DDIAS shields single-stranded DNA in mitosis and promotes vertebrate brain development], CC BY NC 4.0 (https://creativecommons.org/licenses/by-nc/4.0/).
This protective function may be particularly important in cancers with existing DNA repair defects. Tumours lacking functional BRCA1 or BRCA2 have impaired homologous recombination. As a result, these cells accumulate replication-associated DNA lesions and have an increased requirement for mechanisms that protect unresolved DNA damage during cell division.
The researchers found that BRCA1- or BRCA2-deficient cells were highly dependent on DDIAS. Combined loss of DDIAS and BRCA1 or BRCA2 led to a marked increase in micronuclei and significantly reduced cell survival.
The study’s co-lead, Dr Fena Ochs from the University of Copenhagen, said:
“Our results indicate that the chromosome instability caused by loss of homologous recombination becomes lethal when DDIAS-mediated DNA protection is also disrupted. This suggests that inhibiting DDIAS, or other components of the pathway, could represent a potential strategy for selectively targeting BRCA-mutant cancers.”
The researchers also demonstrated a critical role for DDIAS in limiting DNA damage during neurodevelopment. Loss of DDIAS reduced cerebral organoid growth, increases DNA damage and chromosomal instability in neural progenitor cells, and caused a microcephaly-like phenotype in zebrafish. Neural progenitor cells were particularly vulnerable, with DDIAS-deficient cells showing a pronounced increase in micronuclei even in the absence of externally induced DNA damage. This effect was not observed in undifferentiated induced pluripotent stem cells.
Overall, the study establishes DDIAS as a DNA-binding effector of the TOPBP1–CIP2A complex that protects ssDNA lesions from aberrant processing during mitosis, particularly in BRCA-deficient cells and neural stem cells. Further work will investigate whether this dependency can be exploited therapeutically, including whether targeting DDIAS or the wider pathway could provide a new approach to treating BRCA-mutant cancers.
'DDIAS shields single-stranded DNA in mitosis and promotes vertebrate brain development' was published in Cell on the 24th August, 2026.