Ultraviolet-Induced DNA Damage Promotes RNA m⁶A Methylation

The DNA damage response (DDR) detects and repairs DNA damage and halts cell division until the DNA damage is repaired. Chromatin modifications render the damaged region accessible to repair machinery and prevent gene transcription using the damaged template. Xiang, Laurent, Hsu, and colleagues performed a screen to identify chromatin modifications and modifying factors involved in the DDR. DNA damage induced by UV radiation was associated with rapid accumulation of methylation at the 6 position of adenosine (m⁶A) in RNA at DNA damage sites. The m⁶A accumulation was specific to UV-induced damage, dose-dependent, and peaked two minutes after irradiation, with accumulation detectable on poly(A)⁺ RNA. The m⁶A methyltransferase METTL3 was responsible for RNA m⁶A methylation in response to UV-induced DNA damage, and the demethylase FTO opposed METTL3 to remove m⁶A at DNA damage sites. METTL3 catalytic activity enhanced the survival of cells after UV irradiation, and loss of METTL3 resulted in increased UV sensitivity. Mechanistically, METTL3 promoted immediate recruitment of the DNA polymerase Pol κ, which is involved in both nucleotide excision repair and trans-lesion synthesis pathways. Pol κ recruitment to damage sites is compromised by the loss of METTL3 catalytic activity and is associated with delayed removal of cyclobutane pyrimidine dimers, the main lesion induced by UV exposure. Notably, the METTL3/m⁶A-mediated recruitment of Pol κ occurred more rapidly than recruitment of the classic RAD18/PCNA components, suggesting that Pol κ might be acting through a noncanonical DNA repair pathway. Taken together, these results describe an unexpected role for RNA methylation in facilitating repair of UV-induced DNA lesions, thereby promoting resistance to UV damage and cell survival.

Xiang Y, Laurent B, Hsu CH, Nachtergaele S, Lu Z, Sheng W, et al. RNA m⁶A methylation regulates the ultraviolet-induced DNA damage response. Nature 2017;543:573–6.

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