Arginine methylation controls growth regulation by E2F-1

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.

Overexpression of PRMT5 Promotes Tumor Cell Growth and Is Associated with Poor Disease Prognosis in Epithelial Ovarian Cancer

“…PRMT5 can methylate H3R8 and H4R3 to induce silencing of tumor suppressor genes, such as ST7 and NM23 (Pal et al 2004). In addition, it has been shown to interact with many other genes, such as p53 (Scoumanne et al 2009), E2F-1 (Cho et al 2012), IL-2 , cyclin E1 (Fabbrizio et al 2002), TRAIL receptor (Tanaka et al 2009), the CDK4 complex (Aggarwal et al 2010), and E-cadherin (Hou et al 2008), to participate in many cellular processes. In humans, PRMT5 is widely expressed in many organs (such as heart, muscle, and testis) at different levels (Pollack et al 1999).…”

“…These two types of enzymes catalyze the formation of a mono-methylated (MMA) intermediate; subsequently, type I PRMTs (PRMT1, 3, 4, 6, and 8) further catalyze the production of asymmetric dimethylation of arginine residues (aDMA), and type II PRMTs (PRMT5, 7, and 9) catalyze the formation of symmetric dimethylation of arginine residues (sDMA) (Bedford 2007). Arginine methyltransferase 5 (PRMT5), the first identified type II enzyme (Branscombe et al 2001), is 637 amino acids long and maps to in human chromosome 14q11.2 (Krause et al 2007) and is involved in a variety of biological processes, including ribosome biogenesis (Ren et al 2010), assembly of the Golgi apparatus (Zhou et al 2010), cellular differentiation (Dacwag et al 2007(Dacwag et al , 2009Mallappa et al 2011), cellular proliferation (Scoumanne et al 2009), apoptosis (Cho et al 2012), and germ cell specification (Ancelin et al 2006;Eckert et al 2008). PRMT5 can methylate H3R8 and H4R3 to induce silencing of tumor suppressor genes, such as ST7 and NM23 (Pal et al 2004).…”

Inhibition of Cardiomyocyte Hypertrophy by Protein Arginine Methyltransferase 5

“…For example, methylation of histone protein by PRMT5 can regulate DNA damage repairing, gene expression, and RNA splicing (14). Methylation of non-histone proteins, such as p53, HOXA9, NF-B, and E2F-1, by PRMT5 has been implicated in the regulation of cell growth, apoptosis, and inflammation (15)(16)(17). PRMT5 is widely expressed in different human tissues, with high expression levels observed in heart, skeletal muscle, and testis (18,19).…”

Investigation Into the Role of C17orf79/COPR5 in E2F/DP Target Gene Overexpression in NF1 Microdeletion Syndrome

“…The first involved the de-repression of the critical cell cycle regulator CCNE1 and perhaps other E2F/DP regulated genes upon reductions in PRMT5/COPRS-mediated H4R3 dimethylation. The second mechanism was based on the finding that PRMT5 can directly methylate E2F1, leading to its stabilization [4]. Although COPRS had not been implicated in this second pathway, we speculated that a reduction in PRMT5/COPRS complex formation might increase the ability of PRMT5 to stabilize E2F1.…”