Abstract
We have discovered the first two RNA demethylases: FTO, a protein associated with human fat mass obesity and development, and ALKBH5, a protein that affects spermatogenesis in a mouse model. These two proteins catalyze oxidative demethylation of the most prevalent internal modifications of mammalian messenger RNA (mRNA) and other nuclear RNA, N6‐methyladenosine (m6A). These results indicate that reversible RNA modification could impact biological regulation analogous to the well‐known reversible DNA and histone chemical modifications. We have also identified and characterized proteins that can selectively recognize m6A‐modified mRNA and affect the translation status and lifetime of the target mRNA, as well as molecular machines that deposit the m6A methylation on nuclear RNA. Our discoveries indicate the presence of a new mode of biological regulation that depends on reversible and dynamic RNA modifications.
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