THO complex deficiency impairs DNA double-strand break repair via the RNA surveillance kinase SMG-1.

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Kamp JA, Lemmens BBLG, Romeijn RJ, González-Prieto R, Olsen JV, Vertegaal ACO, van Schendel R, Tijsterman M

Nucleic Acids Res. 50 (11) 6235-6250 [2022-06-24; online 2022-06-08]

The integrity and proper expression of genomes are safeguarded by DNA and RNA surveillance pathways. While many RNA surveillance factors have additional functions in the nucleus, little is known about the incidence and physiological impact of converging RNA and DNA signals. Here, using genetic screens and genome-wide analyses, we identified unforeseen SMG-1-dependent crosstalk between RNA surveillance and DNA repair in living animals. Defects in RNA processing, due to viable THO complex or PNN-1 mutations, induce a shift in DNA repair in dividing and non-dividing tissues. Loss of SMG-1, an ATM/ATR-like kinase central to RNA surveillance by nonsense-mediated decay (NMD), restores DNA repair and radio-resistance in THO-deficient animals. Mechanistically, we find SMG-1 and its downstream target SMG-2/UPF1, but not NMD per se, to suppress DNA repair by non-homologous end-joining in favour of single strand annealing. We postulate that moonlighting proteins create short-circuits in vivo, allowing aberrant RNA to redirect DNA repair.

PubMed 35670662

DOI 10.1093/nar/gkac472

Crossref 10.1093/nar/gkac472

pmc: PMC9226523
pii: 6603656