p53-dependent DNA repair during the DNA damage response requires actin nucleation by JMY

The tumour suppressor p53 is a nuclear transcription factor with key roles during DNA damage to enable a variety of cellular responses including cell cycle arrest, apoptosis and DNA repair. JMY is an actin nucleator and DNA damage-responsive protein whose sub-cellular localisation is responsive to stress and during DNA damage JMY undergoes nuclear accumulation. To gain an understanding of the wider role for nuclear JMY in transcriptional regulation, we performed transcriptomics to identify JMY-mediated changes in gene expression during the DNA damage response. We show that JMY is required for effective regulation of key p53 target genes involved in DNA repair, including XPC, XRCC5 (Ku80) and TP53I3 (PIG3). Moreover, JMY depletion or knockout leads to increased DNA damage and nuclear JMY requires its Arp2/3-dependent actin nucleation function to promote the clearance of DNA lesions. In human patient samples a lack of JMY is associated with increased tumour mutation count and in cells results in reduced cell survival and increased sensitivity to DNA damage response kinase inhibition. Collectively, we demonstrate that JMY enables p53-dependent DNA repair under genotoxic stress and suggest a role for actin in JMY nuclear activity during the DNA damage response.

Automated summary

The tumor suppressor p53 plays a crucial role in the cellular response to DNA damage, including cell cycle arrest, apoptosis, and DNA repair. JMY, an actin nucleator and DNA damage-responsive protein, undergoes nuclear accumulation during DNA damage. Through transcriptomics, we identified that JMY is required for the regulation of key p53 target genes involved in DNA repair. Lack or knockout of JMY leads to increased DNA damage and JMY's actin nucleation function is necessary for promoting the clearance of DNA lesions. This study suggests a role for actin in JMY's nuclear activity during the DNA damage response.