Dynamic m6A mRNA methylation directs translational control of heat shock response

By Jun Zhou, Ji Wan, Xiangwei Gao, Xingqian Zhang, Shu‐Bing Qian. Nature, 2015

1,041 citations recorded by the source corpus.

The most abundant mRNA post-transcriptional modification is N6-methyladenosine (m6A), which has broad roles in RNA biology. In mammalian cells, the asymmetric distribution of m6A along mRNAs results in relatively less methylation in the 5′ untranslated region (5′UTR) compared to other regions. However, whether and how 5′UTR methylation is regulated is poorly understood. Despite the crucial role of the 5′UTR in translation initiation, very little is known about whether m6A modification influences mRNA translation. Here we show that in response to heat shock stress, certain adenosines within the 5′UTR of newly transcribed mRNAs are preferentially methylated. We find that the dynamic 5′UTR methylation is a result of stress-induced nuclear localization of YTHDF2, a well-characterized m6A ‘reader’. Upon heat shock stress, the nuclear YTHDF2 preserves 5′UTR methylation of stress-induced transcripts by limiting the m6A ‘eraser’ FTO from demethylation. Remarkably, the increased 5′UTR methylation in the form of m6A promotes cap-independent translation initiation, providing a mechanism for selective mRNA translation under heat shock stress. Using Hsp70 mRNA as an example, we demonstrate that a single m6A modification site in the 5′UTR enables translation initiation independent of the 5′ end N7-methylguanosine cap. The elucidation of the dynamic features of 5′UTR methylation and its critical role in cap-independent translation not only expands the breadth of physiological roles of m6A, but also uncovers a previously unappreciated translational control mechanism in heat shock response.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/e7edbe8dc78624c797ede0ef773de13db0b61dbc

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

In Molecular Biology

Citations in the corpus

Small-molecule targeting of oncogenic FTO demethylase in acute myeloid leukemia (2019, background): “Precise regulation of the m6A modification on RNAs plays important roles in various biological and pathological processes (Fustin et al., 2013; Geula et al., 2015; Lichinchi et al., 2016; Wang et al., 2014b; Xiang et al., 2017; Zheng et al., 2013; Zhou et al., 2015).”
Where, when and how: context-dependent functions of RNA methylation writers, readers, and erasers (2019, background): “…the relevant substrate, including but not limited to facilitating the 3T3-L1 cell differentiation (Zhao et al., 2014); responding to heat shock (Zhou et al., 2015) and UV damage (Xiang et al., 2017); regulating the hepatitis C virus infection (Gokhale et al., 2016); promoting the growth and…”
METTL3 promotes translation in human cancer cells (2016, background): “…and a metagene analysis revealed that m6A peaks were predominantly localized near stop codons, with a subset of m6A peaks located in the 50 UTR and internal exons (Figures 1A and 1B) (Dominissini et al., 2012; Meyer et al., 2012, 2015; Schwartz et al., 2014; Wang et al., 2014c; Zhou et al., 2015).”
Rethinking m6A Readers, Writers, and Erasers (2017, background): “Studies from our group have shown that methylation of cellular 5´UTRs is triggered by diverse stress-response pathways that are often activated in human disease (Meyer et al. 2015, Zhou et al. 2015).”