Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 1785-1797 |
| Number of pages | 13 |
| Journal | EMBO Journal |
| Volume | 31 |
| Issue number | 7 |
| DOIs | |
| Publication status | Published - Apr 4 2012 |
| Externally published | Yes |
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Keywords
- Arginine methylation
- cancer
- E2F-1
- growth control
ASJC Scopus subject areas
- Molecular Biology
- Biochemistry, Genetics and Molecular Biology(all)
- Immunology and Microbiology(all)
- Neuroscience(all)
Cite this
Arginine methylation controls growth regulation by E2F-1. / Cho, Er Chieh; Zheng, Shunsheng; Munro, Shonagh; Liu, Geng; Carr, Simon M.; Moehlenbrink, Jutta; Lu, Yi Chien; Stimson, Lindsay; Khan, Omar; Konietzny, Rebecca; McGouran, Joanna; Coutts, Amanda S.; Kessler, Benedikt; Kerr, David J.; Thangue, Nicholas B La.
In: EMBO Journal, Vol. 31, No. 7, 04.04.2012, p. 1785-1797.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Arginine methylation controls growth regulation by E2F-1
AU - Cho, Er Chieh
AU - Zheng, Shunsheng
AU - Munro, Shonagh
AU - Liu, Geng
AU - Carr, Simon M.
AU - Moehlenbrink, Jutta
AU - Lu, Yi Chien
AU - Stimson, Lindsay
AU - Khan, Omar
AU - Konietzny, Rebecca
AU - McGouran, Joanna
AU - Coutts, Amanda S.
AU - Kessler, Benedikt
AU - Kerr, David J.
AU - Thangue, Nicholas B La
PY - 2012/4/4
Y1 - 2012/4/4
N2 - 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.
AB - 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.
KW - Arginine methylation
KW - cancer
KW - E2F-1
KW - growth control
UR - http://www.scopus.com/inward/record.url?scp=84862812370&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84862812370&partnerID=8YFLogxK
U2 - 10.1038/emboj.2012.17
DO - 10.1038/emboj.2012.17
M3 - Article
C2 - 22327218
AN - SCOPUS:84862812370
VL - 31
SP - 1785
EP - 1797
JO - EMBO Journal
JF - EMBO Journal
SN - 0261-4189
IS - 7
ER -