Mitotic processing of under-replicated DNA can cause Sister Chromatid Exhanges

PARP inhibitors are used in the clinic to treat patients with breast or ovarian cancers, when these tumors have a defect in homologous recombination DNA. With this concept in mind, we performed a series of experiments to measure how PARP inhibition would activate the HR repair pathway. We then stumbled on some unexpected findings.
Cells with UFB's

When measuring Sister Chromatid Exchange (SCE) rates, a well-established assay to study homologous recombination repair, we observed that PARP inhibition led to a marked elevation of SCEs, exactly as expected. However, we surprisingly found that PARP inhibition also induced SCEs in absence of BRCA1, BRCA2 and Rad51 – all essential proteins for HR.

Using genome-wide mapping of SCEs using StrandSeq, developed by the research group of Peter Lansdorp at the ERIBA, we observed that SCEs were enriched at areas of the genome that are difficult to replicate. In line with this observation, our follow-up experiments showed that many agents that perturb replication induce SCEs, independently of HR.

In collaboration with the lab of Puck Knipscheer at the Hubrecht Institute and the research group of Ruben van Boxtel at the Princess Maxima Center in Utrecht, we established that mitotic processing of under-replicated DNA can cause SCEs, very likely involving Polymerase Theta-mediated end joining. The subsequent genomic scar in tumor genomes was found frequently in a cohort of breast cancers, underscoring that this mechanism may be relevant in shaping tumor genomes, and allowing cancer cells to survive defects in DNA replication.

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Sister chromatid exchanges induced by perturbed replication can form independently of BRCA1, BRCA2 and RAD51