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Nature. 2017 Mar 23;543(7646):573-576. doi: 10.1038/nature21671. Epub 2017 Mar 15.

RNA m6A methylation regulates the ultraviolet-induced DNA damage response.

Xiang Y1,2, Laurent B1,2, Hsu CH1,2, Nachtergaele S3,4,5, Lu Z3,4,5, Sheng W1,2, Xu C1,2, Chen H1,2, Ouyang J6,7, Wang S1,2, Ling D1,2, Hsu PH8, Zou L6,7, Jambhekar A1,2, He C3,4,5, Shi Y1,2.

Author information

1
Division of Newborn Medicine and Epigenetics Program, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
2
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
3
Department of Chemistry, University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA.
4
Institute for Biophysical Dynamics, University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA.
5
Howard Hughes Medical Institute, University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA.
6
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02109, USA.
7
Department of Pathology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02109, USA.
8
Department of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung City 202, Taiwan.

Abstract

Cell proliferation and survival require the faithful maintenance and propagation of genetic information, which are threatened by the ubiquitous sources of DNA damage present intracellularly and in the external environment. A system of DNA repair, called the DNA damage response, detects and repairs damaged DNA and prevents cell division until the repair is complete. Here we report that methylation at the 6 position of adenosine (m6A) in RNA is rapidly (within 2 min) and transiently induced at DNA damage sites in response to ultraviolet irradiation. This modification occurs on numerous poly(A)+ transcripts and is regulated by the methyltransferase METTL3 (methyltransferase-like 3) and the demethylase FTO (fat mass and obesity-associated protein). In the absence of METTL3 catalytic activity, cells showed delayed repair of ultraviolet-induced cyclobutane pyrimidine adducts and elevated sensitivity to ultraviolet, demonstrating the importance of m6A in the ultraviolet-responsive DNA damage response. Multiple DNA polymerases are involved in the ultraviolet response, some of which resynthesize DNA after the lesion has been excised by the nucleotide excision repair pathway, while others participate in trans-lesion synthesis to allow replication past damaged lesions in S phase. DNA polymerase κ (Pol κ), which has been implicated in both nucleotide excision repair and trans-lesion synthesis, required the catalytic activity of METTL3 for immediate localization to ultraviolet-induced DNA damage sites. Importantly, Pol κ overexpression qualitatively suppressed the cyclobutane pyrimidine removal defect associated with METTL3 loss. Thus, we have uncovered a novel function for RNA m6A modification in the ultraviolet-induced DNA damage response, and our findings collectively support a model in which m6A RNA serves as a beacon for the selective, rapid recruitment of Pol κ to damage sites to facilitate repair and cell survival.

PMID:
28297716
PMCID:
PMC5490984
DOI:
10.1038/nature21671
[Indexed for MEDLINE]
Free PMC Article

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