The RNA m5C modification in R-loops as an off switch of Alt-NHEJ

Haibo Yang, Emily M. Lachtara, Xiaojuan Ran, Jessica Hopkins, Parasvi S. Patel, Xueping Zhu, Yao Xiao, Laiyee Phoon, Boya Gao, Lee Zou, Michael S. Lawrence and Li Lan ()
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Haibo Yang: Harvard Medical School
Emily M. Lachtara: Harvard Medical School
Xiaojuan Ran: Harvard Medical School
Jessica Hopkins: Harvard Medical School
Parasvi S. Patel: Harvard Medical School
Xueping Zhu: Harvard Medical School
Yao Xiao: Harvard Medical School
Laiyee Phoon: Duke University
Boya Gao: Harvard Medical School
Lee Zou: Harvard Medical School
Michael S. Lawrence: Harvard Medical School
Li Lan: Harvard Medical School

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract The roles of R-loops and RNA modifications in homologous recombination (HR) and other DNA double-stranded break (DSB) repair pathways remain poorly understood. Here, we find that DNA damage-induced RNA methyl-5-cytosine (m5C) modification in R-loops plays a crucial role to regulate PARP1-mediated poly ADP-ribosylation (PARylation) and the choice of DSB repair pathways at sites of R-loops. Through bisulfite sequencing, we discover that the methyltransferase TRDMT1 preferentially generates m5C after DNA damage in R-loops across the genome. In the absence of m5C, R-loops activate PARP1-mediated PARylation both in vitro and in cells. Concurrently, m5C promotes transcription-coupled HR (TC-HR) while suppressing PARP1-dependent alternative non-homologous end joining (Alt-NHEJ), favoring TC-HR over Alt-NHEJ in transcribed regions as the preferred repair pathway. Importantly, simultaneous disruption of both TC-HR and Alt-NHEJ with TRDMT1 and PARP or Polymerase θ inhibitors prevents alternative DSB repair and exhibits synergistic cytotoxic effects on cancer cells, suggesting an effective strategy to exploit genomic instability in cancer therapy.

Date: 2023
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DOI: 10.1038/s41467-023-41790-w

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