期刊
EMBO JOURNAL
卷 31, 期 7, 页码 1785-1797出版社
WILEY
DOI: 10.1038/emboj.2012.17
关键词
arginine methylation; cancer; E2F-1; growth control
资金
- CRUK
- MRC
- LLR
- EU
- Agency for Science, Technology and Research of Singapore
- Biomedical Research Centre (NIHR), Oxford, UK
- Cancer Research UK [13058] Funding Source: researchfish
- Medical Research Council [G0500905, G9400953] Funding Source: researchfish
- MRC [G0500905, G9400953] Funding Source: UKRI
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. The EMBO Journal (2012) 31, 1785-1797. doi: 10.1038/emboj.2012.17; Published online 10 February 2012
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