5-methylcytosine modification by Plasmodium NSUN2 stabilizes mRNA and mediates the development of gametocytes

Significance Modifications of RNA, including methylations of cytosine (m 5 C) and adenosine (m 6 A), have important roles in RNA metabolism, cellular responses to stress, and biological processes of differentiation and development. We report on the profiles of m 5 C messenger RNA (mRNA) modifications in malaria parasites that infect rodents ( Plasmodium yoelii ) and humans ( Plasmodium falciparum ). These parasites have genes that encode homologs of human and plant NSUN2 methyltransferases (m 5 C “writers”). We show that one of these homologs, termed PyNSUN2, stabilizes mRNA transcripts in P. yoelii and mediates m 5 C-associated development of the parasite sexual stages (gametocytes). Further research on m 5 C and other epitranscriptomic modifications may yield new insights into molecular pathways of gametocyte development and mosquito infectivity that can be exploited to interrupt malaria transmission.