Differential Methylation Determines the Role of E2F1 in Growth Control

The transcription factor E2F1 promotes cell-cycle progression by activating the expression of proliferative genes but has also been shown to stimulate apoptosis in response to DNA damage. Although methylation of E2F1 by protein arginine methyltransferase 5 (PRMT5) has recently been suggested to regulate E2F1 activity, the mechanisms that control the outcome of E2F1 signaling with regard to its opposing biologic functions remain poorly understood. Zheng and colleagues found that, in addition to PRMT5, E2F1 also interacts with PRMT1, which mediates asymmetric arginine methylation of E2F1. PRMT1 and PRMT5 competitively interacted with E2F1, such that PRMT1 methylation at R109 and PRMT5 methylation at R111/R113 reciprocally interfered with each other and differentially affected E2F1 protein stability, suggesting that these modifications antagonistically modulate E2F1 function. Consistent with this idea, PRMT1-mediated asymmetric methylation promoted E2F1 transcriptional regulation of proapoptotic genes and E2F1-induced apoptosis, whereas PRMT5-driven symmetric methylation inhibited these genes and stimulated cell growth. DNA damage activated E2F1-induced apoptosis by enhancing the interaction of E2F1 with PRMT1, leading to increased R109 methylation and attenuated PRMT5 methylation of R111/R113. In contrast, cyclin A binding to E2F1 prevented PRMT1 binding and augmented the E2F1–PRMT5 interaction and PRMT5 methylation of R111/R113, resulting in inhibition of apoptosis and increased cell viability. This switch in E2F1 activity to promote proliferation and suppress apoptosis was dependent on the Tudor domain protein p100-TSN (also known as staphylococcal nuclease and Tudor domain containing 1), a methylation reader that specifically bound to symmetrically methylated E2F1 at R111/R113 and was present at the promoters of E2F1 target genes involved in cell-cycle progression. Together, these findings identify residue-specific arginine methylation and the interplay between readers and writers of these modifications as critical determinants of the outcome of E2F1 activity.

Zheng S, Moehlenbrink J, Lu YC, Zalmas LP, Sagum CA, Carr S, et al. Arginine methylation-dependent reader-writer interplay governs growth control by E2F-1. Mol Cell 2013;52:37–51.

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