THO complex deficiency impairs DNA double-strand break repair via the RNA surveillance kinase SMG-1
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THO complex deficiency impairs DNA double-strand break repair via the RNA surveillance kinase SMG-1. / Kamp, Juliette A; Lemmens, Bennie B L G; Romeijn, Ron J; González-Prieto, Román; Olsen, Jesper V.; Vertegaal, Alfred C O; van Schendel, Robin; Tijsterman, Marcel.
In: Nucleic Acids Research, Vol. 50, No. 11, 2022, p. 6235-6250.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - THO complex deficiency impairs DNA double-strand break repair via the RNA surveillance kinase SMG-1
AU - Kamp, Juliette A
AU - Lemmens, Bennie B L G
AU - Romeijn, Ron J
AU - González-Prieto, Román
AU - Olsen, Jesper V.
AU - Vertegaal, Alfred C O
AU - van Schendel, Robin
AU - Tijsterman, Marcel
N1 - © The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
U2 - 10.1093/nar/gkac472
DO - 10.1093/nar/gkac472
M3 - Journal article
C2 - 35670662
VL - 50
SP - 6235
EP - 6250
JO - Nucleic Acids Research
JF - Nucleic Acids Research
SN - 0305-1048
IS - 11
ER -
ID: 310852975