Four weeks ago, we shared a report [discussed below; and first attachment] about the discovery of chemical tags on RNA (as well as DNA) that probably participate in the mechanisms involving epigenetics. The present article [second attachment] describes a practical example where RNA-methylation indeed appears to be participating in downstream signaling pathways (in which “the signal” is UV-induced DNA damage).
The proliferation and survival of cells require the faithful maintenance and propagation of genetic information –– which are continuously threatened by the ubiquitous sources of DNA damage, caused both intracellularly and by external environment “stressor signals.” A system of DNA repair, called “the DNA damage response,” detects and repairs damaged DNA and prevents cell division until DNA repair is complete.
Authors in the latest attachment 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 (UV) 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 UV-induced cyclobutane-pyrimidine adducts and elevated sensitivity to UV, demonstrating the importance of m6A in the UV-induced DNA damage response. Multiple DNA polymerases are involved in the UV 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 synthesis phase) of the cell cycle. DNA polymerase κ (Pol κ), which has been implicated in both nucleotide-excision repair and trans-lesion synthesis, requires the catalytic activity of METTL3 for immediate localization to UV-induced DNA-damage sites. Importantly, Pol κ over-expression qualitatively suppressed cyclobutane-pyrimidine removal defects associated with METTL3 ablation.
Thus, authors have uncovered a novel function for RNA- m6A modification in the UV-induced DNA-damage response, collectively supporting a model in which m6A RNA serves as a beacon for the selective, rapid recruitment of Pol κ to DNA-damage sites –– in order to facilitate DNA-repair and cell-survival. These findings therefore demonstrate a function for the discovery reported just a month ago..!!
Nature 23 Mar 2o17; 543: 573-576