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Research by Professor Yang Shi and colleagues sheds light on the molecular mechanism of N6-adenosine methylation by METTL4, which may be shared by related RNA methyltransferases known to be involved in cancer.

RNA can be chemically modified by the addition of methyl group(s), representing an important epigenetic mechanism by which to regulate several cellular processes. This is evidenced by the involvement of abnormal RNA methylation in human diseases such as cancer.

Several RNA-modifying enzymes have been discovered. One of these, called METTL4, has been shown to methylate a number of RNA targets. Despite this previous research, the exact target of METTL4 is still unclear, especially whether there is selectivity for prior RNA modification, partly due to the lack of structural evidence of METTL4 with the proposed RNA substrates.

To address this question, Ludwig Oxford’s Professor Yang Shi and colleagues from Fudan University and the Chinese Academy of Sciences determined the structure of the full-length METTL4 protein from the plant model organism Arabidopsis in complex with the methyl donor S-adenosyl-L-methionine (SAM) and a co-structure of METTL4 bound to an RNA substrate with the prior modification 2’-O-methyladenosine in the presence of S-adenosyl-L-homocysteine (SAH; the by-product formed following transfer of the methyl group from SAM to the RNA substrate).

These structures, with associated biochemical and modelling analysis, give insight into the substrate specificity and catalytic mechanism of METTL4, which may be shared among other members of the METTL4 methyltransferase family, including those known to be involved in cancer.

 

Read the full paper in Nature Communications.

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