A major advance in cell biology has revealed how our cells safeguard their genetic material during one of the most vulnerable moments in their life cycle. The study identifies a specific protein complex as a central coordinator of DNA repair during cell division.
Every time a cell divides, it must copy its entire DNA and distribute it evenly between two daughter cells. This process, called mitosis, is usually tightly regulated. However, if cells enter mitosis with unfinished or damaged DNA, chromosomes can break apart, leading to genetic instability – a hallmark of many diseases, including cancer. Until now, scientists did not fully understand how cells manage DNA damage during mitosis, when most conventional repair systems are switched off.
Now, researchers have shown that the protein complex CIP2A–TOPBP1 plays a key part in managing DNA repair processes during mitosis. This discovery provides crucial insight into how cells maintain genome stability and offers promising new directions for cancer treatment.
Scientists from The Institute of Cancer Research, London, led the study, the findings of which were published in the journal Nature Communications. The work was funded by the Medical Research Council, the Biotechnology and Biological Sciences Research Council, Cancer Research UK, the Wellcome Trust, the Royal Society and The Institute of Cancer Research (ICR), which is both a research institute and a charity.
The challenge of DNA repair in mitosis
DNA repair during mitosis is uniquely challenging. The usual repair pathways, which operate during earlier phases of the cell cycle, are largely inactive. Instead, cells rely on emergency mechanisms to prevent catastrophic chromosome breakage. Two such backup systems – mitotic DNA synthesis (MiDAS) and microhomology-mediated end joining (MMEJ) – step in to resolve replication stress and repair DNA breaks. The new study demonstrates that these processes are not random but precisely orchestrated by the CIP2A–TOPBP1 axis.
The CIP2A-TOPBP1 protein duo acts as a molecular coordinator, ensuring that MiDAS and MMEJ occur at the right time and place. The choreography is remarkably precise: a single amino acid change in one of the repair proteins this complex controls, SLX4, can disrupt the localisation of repair machinery specifically in mitosis, destabilising chromosomes and slowing cell growth. These findings underscore the complexity of mitotic DNA repair and highlight potential vulnerabilities that could be exploited in cancer therapy.
A collaborative scientific approach
The research represents a highly collaborative, multidisciplinary effort. The team used a combination of innovative techniques – including advanced light microscopy, flow cytometry, proteomics, gene editing and biochemical analysis – to unravel the intricate processes that protect chromosomes during division.
This integration of cutting-edge technologies was essential to observe DNA repair events in real time and map the molecular interactions that maintain genome stability.
Implications for cancer research
The clinical significance of this discovery is profound. Cancer cells often endure high levels of replication stress and DNA damage, but they survive by hijacking backup repair pathways. The study reveals that tumours deficient in BRCA1 or BRCA2 – genes essential for homologous recombination repair – or exposed to drugs that induce DNA damage are particularly dependent on the CIP2A–TOPBP1 axis. Disrupting this dependency could render such cancers unable to repair their DNA, leading to cell death.
The findings challenge previous assumptions about CIP2A. Earlier studies suggested that CIP2A primarily acted as a structural tether in mitosis, holding broken chromosomes together during cell division. These new data reveal that CIP2A actively regulates MiDAS and MMEJ, underlining another critical function of this complex.
This previously unknown role highlights the dynamic nature of mitotic repair and suggests opportunities for highly selective interventions that disrupt cancer-specific vulnerabilities without harming normal cells.
Future directions
Building on these findings, the researchers plan to chart the mechanisms that maintain genome stability during mitosis, which remain relatively undefined. Through this, their ultimate goal is to identify novel therapeutic targets that exploit cell-cycle-specific weaknesses, improving outcomes for patients with cancers that currently lack effective treatment options.
First author Dr Peter Martin, Senior Scientific Officer in the Division of Cell and Molecular Biology at the ICR, said:
“The significant role that CIP2A has in maintaining genome stability through DNA repair was unexpected, but it opens the door to new therapeutic possibilities, with CIP2A, TOPBP1 and SLX4 among the proteins emerging as promising drug targets.
“The next step is to define biomarkers of DNA damage tolerance in mitosis, so clinicians can select patients that may benefit the most from therapies that target these processes. Over time, we hope to reshape treatment paradigms for cancers that are driven by replication stress or resistant to conventional chemotherapies, improving patient outcomes especially for those with unmet clinical needs.”
Senior author Professor Wojciech Niedzwiedz, Group Leader of the Cancer and Genome Instability Group at the ICR, said:
“By focusing on mitosis – a critical yet underexplored phase – this research opens a new frontier in cancer biology and therapeutic innovation. Deepening our understanding of mitotic DNA repair is key for developing strategies that synergise with existing treatments and overcome resistance to first-line therapies.
“Our longer-term aim is to significantly improve treatment outcomes for patients, giving more people extra time to enjoy in better health.”
Image credit: Mahmoud Ahmed from Pixabay