Dynamic RNA Modifications in Gene Expression Regulation

Where, When, and How: Context-Dependent Functions of RNA Methylation Writers, Readers, and Erasers

Alternative splicing of eukaryotic transcripts is a mechanism that enables cells to generate vast protein diversity from a limited number of genes. The mechanisms and outcomes of alternative splicing of individual transcripts are relatively well understood, and recent efforts have been directed towards studying splicing networks. It has become apparent that coordinated splicing networks regulate tissue and organ development, and that alternative splicing has important physiological functions in different developmental processes in humans.

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Alternative splicing as a regulator of development and tissue identity

N6-methyladenosine (m6A) is identified as the most common, abundant and conserved internal transcriptional modification, especially within eukaryotic messenger RNAs (mRNAs). M6A modification is installed by the m6A methyltransferases (METTL3/14, WTAP, RBM15/15B and KIAA1429, termed as “writers”), reverted by the demethylases (FTO and ALKBH5, termed as “erasers”) and recognized by m6A binding proteins (YTHDF1/2/3, IGF2BP1 and HNRNPA2B1, termed as “readers”). Acumulating evidence shows that, m6A RNA methylation has an outsize effect on RNA production/metabolism and participates in the pathogenesis of multiple diseases including cancers. Until now, the molecular mechanisms underlying m6A RNA methylation in various tumors have not been comprehensively clarified. In this review, we mainly summarize the recent advances in biological function of m6A modifications in human cancer and discuss the potential therapeutic strategies.

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The role of m 6 A RNA methylation in human cancer

m6A Modification in Coding and Non-coding RNAs: Roles and Therapeutic Implications in Cancer

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.

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

A Specific LSD1/KDM1A Isoform Regulates Neuronal Differentiation through H3K9 Demethylation

Nature 543, 573–576 (2017); doi:10.1038/nature21671 In Extended Data Fig. 4d of this Letter, the immunofluorescence images (bottom row, experiments performed in the presence of the PARP inhibitor Olaparib) were inadvertently duplicated in panel e (bottom row, under the ‘PARP inhibitor’ heading). Thecorrected Extended Data Fig.

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Yang Xiang

Papers

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

A Specific LSD1/KDM1A Isoform Regulates Neuronal Differentiation through H3K9 Demethylation

Corrigendum: RNA m 6 A methylation regulates the ultraviolet-induced DNA damage response.

Impact of the cold surge event in January 2021 on the power system of China