Abstract
Cross-talk between distinct protein post-translational modifications is critical for an effective DNA damage response. Arginine methylation plays an important role in maintaining genome stability, but how this modification integrates with other enzymatic activities is largely unknown. Here, we identify the deubiquitylating enzyme USP11 as a previously uncharacterised PRMT1 substrate, and demonstrate that the methylation of USP11 promotes DNA end-resection and the repair of DNA double strand breaks (DSB) by homologous recombination (HR), an event that is independent from another USP11-HR activity, the deubiquitylation of PALB2. We also show that PRMT1 is a ubiquitylated protein that it is targeted for deubiquitylation by USP11, which regulates the ability of PRMT1 to bind to and methylate MRE11. Taken together, our findings reveal a specific role for USP11 during the early stages of DSB repair, which is mediated through its ability to regulate the activity of the PRMT1-MRE11 pathway.
Highlights
Cross-talk between distinct protein post-translational modifications is critical for an effective DNA damage response
That USP11 has been implicated in this process[27,28,30,31,32,33,34], we decided to investigate the significance of the PRMT1/USP11 interaction further
We found that ectopically expressed USP11 coimmunoprecipitated endogenous PRMT1 in cells (Fig. 1a) and that this was a direct interaction as determined by in vitro GST pull-down assays using recombinant GST-PRMT1 and recombinant human USP11 (Supplementary Fig. 1b)
Summary
Cross-talk between distinct protein post-translational modifications is critical for an effective DNA damage response. The process of DSB repair, including damage sensing, the choice of repair pathway, and the termination of the repair response, is driven by a plethora of enzymes, including nucleases, polymerases, kinases, phosphatases, methyltransferases and E3 ubiquitin ligases As such, these activities have to be tightly regulated to mitigate any inappropriate action that could be detrimental to the repair process itself. Since PRMT1 is the major enzyme that catalyses cellular methylation and preferentially asymmetrically dimethylated arginine residues embedded within the RG/RGG motif[12,21], PRMT1 substrate identification has largely been carried out through affinity purification using antibodies that recognise asymmetrically dimethylated RG/RGG motifs[22,23] Whilst this approach has identified numerous PRMT1 substrates, including MRE1123, it is clear that some PRMT1 substrates are methylated within non-consensus sites[24,25,26]. Alternative proteomic approaches are required to fully elucidate the substrate repertoire of PRMT1
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