Modulation of m6A RNA modification by DAP3 in cancer cells
Menée à l'aide de lignées cellulaires et de modèles murins, cette étude met en évidence deux mécanismes distincts par lequel la protéine DAP3 favorise la préservation du niveau de N6-méthyladénosine dans les cellules cancéreuses
Dysregulation of N6-methyladenosine (m6A) RNA methylation is prevalent in many cancers. In this study, we demonstrated death dssociated protein 3 (DAP3) as a pivotal global m6A regulator in cancer cells, playing a crucial role in sustaining tumorigenesis by maintaining m6A levels. DAP3 achieves this remarkable m6A modulation through two distinct yet complementary mechanisms. First, DAP3 enhances m6A deposition by facilitating methyltransferase-like 3 (METTL3) binding to m6A sites. Second, DAP3 serves as a regulator of MAT2A splicing, controlling the retention of MAT2A’s last intron and its protein production. This regulation ensures the maintenance of cellular S-adenosylmethionine (SAM) levels necessary to sustain global m6A levels. This finding expands our understanding of the dysregulation of m6A levels during the oncogenic process. N6-methyladenosine (m6A) RNA methylation is a prevalent RNA modification that significantly impacts RNA metabolism and cancer development. Maintaining the global m6A levels in cancer cells relies on RNA accessibility to methyltransferases and the availability of the methyl donor S-adenosylmethionine (SAM). Here, we reveal that death associated protein 3 (DAP3) plays a crucial role in preserving m6A levels through two distinct mechanisms. First, although DAP3 is not a component of the m6A writer complex, it directly binds to m6A target regions, thereby facilitating METTL3 binding. Second, DAP3 promotes MAT2A’s last intron splicing, increasing MAT2A protein, cellular SAM, and m6A levels. Silencing DAP3 hinders tumorigenesis, which can be rescued by MAT2A overexpression. This evidence suggests DAP3’s role in tumorigenesis, partly through m6A regulation. Our findings unveil DAP3’s complex role as an RNA-binding protein and tumor promoter, impacting RNA processing, splicing, and m6A modification in cancer transcriptomes.
Proceedings of the National Academy of Sciences , article en libre accès, 2023