Arginine methylation controls growth regulation by E2F-1.
E2F transcription factors are implicated in diverse cellular functions. The founding member, E2F-1, is endowed with contradictory activities, being able to promote cell-cycle progression and induce apoptosis. However, the mechanisms that underlie the opposing outcomes of E2F-1 activation remain largely unknown. We show here that E2F-1 is directly methylated by PRMT5 (protein arginine methyltransferase 5), and that arginine methylation is responsible for regulating its biochemical and functional properties, which impacts on E2F-1-dependent growth control. Thus, depleting PRMT5 causes increased E2F-1 protein levels, which coincides with decreased growth rate and associated apoptosis. Arginine methylation influences E2F-1 protein stability, and the enhanced transcription of a variety of downstream target genes reflects increased E2F-1 DNA-binding activity. Importantly, E2F-1 is methylated in tumour cells, and a reduced level of methylation is evident under DNA damage conditions that allow E2F-1 stabilization and give rise to apoptosis. Significantly, in a subgroup of colorectal cancer, high levels of PRMT5 frequently coincide with low levels of E2F-1 and reflect a poor clinical outcome. Our results establish that arginine methylation regulates the biological activity of E2F-1 activity, and raise the possibility that arginine methylation contributes to tumourigenesis by influencing the E2F pathway.
Department of Oncology, Laboratory of Cancer Biology, University of Oxford, Oxford, UK.
Er-Chieh
EC
Cho
Shunsheng
S
Zheng
Shonagh
S
Munro
Geng
G
Liu
Simon M
SM
Carr
Jutta
J
Moehlenbrink
Yi-Chien
YC
Lu
Lindsay
L
Stimson
Omar
O
Khan
Rebecca
R
Konietzny
Joanna
J
McGouran
Amanda S
AS
Coutts
Benedikt
B
Kessler
David J
DJ
Kerr
Nicholas B La
NB
Thangue
D017209:Apoptosis; D001120:Arginine / Q000378:metabolism*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008745:Methylation; D011496:Protein Methyltransferases / Q000378:metabolism; D055550:Protein Stability; D011484:Protein-Arginine N-Methyltransferases
D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D001120:Arginine; D011496:Protein Methyltransferases; C400529:PRMT5 protein, human; D011484:Protein-Arginine N-Methyltransferases