When exposed to high temperatures, cells behave much as we would on a hot summer’s day. Cell division, and most energy-consuming activities, come to a standstill (a bit like the human equivalent of lying perfectly still on a sunbed with a mojito in hand). Yet, despite the general repression of translation, genes encoding protective heat shock factors are massively expressed. Now researchers from Cornell University show that by marking specifically heat shock transcripts, m6A RNA methylation helps to protect cells when temperatures get too high.
m6A RNA methylation has been a ‘hot topic’ ever since the realization that it is a dynamic modification that is highly abundant in mammalian cells. It has been implicated in just about every aspect of mRNA metabolism, but reports describing its role in the control of cellular expression programs are only just starting to emerge.
We know that mRNA is not evenly coated with m6A. In particular, m6A is relatively scarce in the 5’UTR of most mRNAs, although it is unclear why. Using a clever series of m6A-sequencing, loss of function experiments, and reporter assays, Qian and colleagues show that following heat shock:
- m6A increases specifically at the 5’UTR of transcripts upregulated in response to stress.
- The m6A methylation reader, YTHDF2, moves from the cytosol to nucleus, where it binds to m6A and protects it from being removed by the m6A eraser enzyme, FTO.
- Cap-dependent translation is suppressed, but m6A in the 5’UTR may act as a cap substitute, enabling the translation of heat shock transcripts.
- In the heat shock gene Hsp70, the researchers show that a single m6A modification enables translation to occur
These findings highlight a surprising role for m6A RNA methylation in translation and may explain how cellular genes lacking internal ribosome entry sites can still be translated via cap-independent translation.
Check out these new findings, (kinda) hot off the press, over at Nature October 2015.