Our genome is constantly being challenged by endogenous and exogenous DNA damaging agents, and a failure to repair such damage leads to genome instability that predisposes individuals to cancer. Somewhat paradoxically, most chemotherapies function by inducing catastrophic DNA damage, hence understanding mechanistically how DNA damage repair pathways are co-ordinated in response to specific DNA damaging agents is essential to understand malignant transformation and chemo-resistance.

 

We have recently described a role for PRMT5 in homologous recombination (HR) repair of double strand breaks through the methylation of the AAA-ATPase RUVBL1 (Clarke et al., Molecular Cell, 2017). We showed that PRMT5 was important for promoting the mobilisation of 53BP1 from DNA break ends, enabling DNA end resection, committing a cell to HR repair.  Mechanistically, we demonstrated that RUVBL1 methylation was an essential component of this by facilitating TIP60-dependent acetylation of histone H4K16, leading to 53BP1 displacement.

 

We are now interested in understanding how PRMT5 regulates other types of DNA damage, including replication stress. This will help us understand if drug targeting PRMT5 in combination with DNA damaging chemotherapies is an effective way in which to kill cancer cells. We are particularly interested in determining if aberrant PRMT5 methylation promotes BRCAness in BRCA1-proficient triple negative breast cancers. We are also determining if PRMT5 activity is dynamically modulated after DNA damage, and if this is dependent on any specific DNA repair signalling pathway.