Phosphoproteomics of C.elegans RNA binding protein mutants

Nonsense-mediated mRNA decay (NMD) monitors the quality of transcriptomes and degrades messenger RNAs containing splicing errors or premature stop codons. NMD thus dictates the severity and outcome of genetic disorders, gene edits and knockouts as well as the prevalence of neoantigens. Central to the NMD pathway are SMG-1, an ATM/ATR-like kinase, and its downstream target SMG-2/UPF1, a highly processive DNA/RNA helicase. Interestingly, many NMD factors acquired additional ‘moonlighting’ functions in the nucleus, including roles in DNA synthesis and DNA damage signalling. While having the same protein controlling RNA and DNA metabolism could be beneficial, it could also lead to signalling conflicts that jeopardize genome stability. Surprisingly little is known about the incidence and impact of such crosstalk in biology, neither in physiological nor in pathological scenarios. Here, via genetics screens and genome-wide analyses, we identified unforeseen crosstalk between RNA surveillance and DNA repair in living animals. Defects in RNA processing, due to viable THO complex or PNN-1 mutations, trigger SMG-1 activity, which causes a major shift in DNA repair and compromises genome stability in somatic tissues. Mechanistically, we find SMG-1 and SMG-2/UPF1, but not NMD per se, to suppress DNA repair by classical non-homologous end-joining while allowing mutagenic repair by single strand annealing. We postulate that aberrant RNA structures trigger crosstalk that re-directs DNA repair and genome evolution.