Arginine methylation-dependent reader-writer interplay governs growth control by E2F-1.
The mechanisms that underlie and dictate the different biological outcomes of E2F-1 activity have yet to be elucidated. We describe the residue-specific methylation of E2F-1 by the asymmetric dimethylating protein arginine methyltransferase 1 (PRMT1) and symmetric dimethylating PRMT5 and relate the marks to different functional consequences of E2F-1 activity. Methylation by PRMT1 hinders methylation by PRMT5, which augments E2F-1-dependent apoptosis, whereas PRMT5-dependent methylation favors proliferation by antagonizing methylation by PRMT1. The ability of E2F-1 to prompt apoptosis in DNA damaged cells coincides with enhanced PRMT1 methylation. In contrast, cyclin A binding to E2F-1 impedes PRMT1 methylation and augments PRMT5 methylation, thus ensuring that E2F-1 is locked into its cell-cycle progression mode. The Tudor domain protein p100-TSN reads the symmetric methylation mark, and binding of p100-TSN downregulates E2F-1 apoptotic activity. Our results define an exquisite level of precision in the reader-writer interplay that governs the biological outcome of E2F-1 activity.
Laboratory of Cancer Biology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Old Road Campus, off Roosevelt Drive, Oxford OX3 7DQ, UK; Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A(∗)STAR (Agency for Science, Technology, and Research), Biopolis, Singapore 138672, Singapore.
Shunsheng
S
Zheng
Jutta
J
Moehlenbrink
Yi-Chien
YC
Lu
Lykourgos-Panagiotis
LP
Zalmas
Cari A
CA
Sagum
Simon
S
Carr
Joanna F
JF
McGouran
Leila
L
Alexander
Oleg
O
Fedorov
Shonagh
S
Munro
Benedikt
B
Kessler
Mark T
MT
Bedford
Qiang
Q
Yu
Nicholas B
NB
La Thangue
D020816:Amino Acid Motifs; D017209:Apoptosis; D001120:Arginine; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D042002:Chromatin Assembly and Disassembly; D019925:Cyclin A / Q000378:metabolism; D004249:DNA Damage; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008745:Methylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D014162:Transfection
D019925:Cyclin A; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D012097:Repressor Proteins; D001120:Arginine; C099988:PRMT1 protein, human; C400529:PRMT5 protein, human; D011484:Protein-Arginine N-Methyltransferases