Lysine Methylation Regulates E2F1-Induced Cell Death

Abstract

Histone-modifying enzymes can regulate DNA damage-induced apoptosis through modulation of p53 function. Here, we show that, in p53-deficient tumor cells, Set9 and LSD1 regulate DNA damage-induced cell death in a manner opposite to that observed in p53(+/+) cells, via modulation of E2F1 stabilization. Set9 methylates E2F1 at lysine-185, which prevents E2F1 accumulation during DNA damage and activation of its proapoptotic target gene p73. This methyl mark is removed by LSD1, which is required for E2F1 stabilization and apoptotic function. The molecular mechanism involves crosstalks between lysine methylation and other covalent modifications that affect E2F1 stability. Methylation at lysine-185 inhibits acetylation and phosphorylation at distant positions and, in parallel, stimulates ubiquitination and degradation of the protein. The findings illustrate that the function of methyltransferases can have opposing biological outcomes depending on the specificity of transcription factor targets.

Diversity within the pRb pathway: is there a code of conduct?

“…Post-translational modifications can hinder or assist the occurrence of other post-translational modifications. In the case of E2F-1, methylation at K185 prevents phosphorylation and acetylation, and promotes ubiquitination (Kontaki and Talianidis, 2010). Likewise, when pRb is targeted by methylation and acetylation, phosphorylation is reduced.…”

“…The histone methyltransferase Set7/9 methylates E2F-1 (Kontaki and Talianidis, 2010). Set7/9 methylates E2F-1 at K185, which although located within the DNA binding domain of E2F-1, does not affect DNA binding activity in in vitro assays.…”

“…Set7/9 methylates E2F-1 at K185, which although located within the DNA binding domain of E2F-1, does not affect DNA binding activity in in vitro assays. There appears to be considerable interplay between methylation and other post-translational modifications; for example, methylation of E2F-1 antagonizes the acetylation and phosphorylation events that are required for its stabilization during the damage response, and methylation triggers ubiquitination and subsequent degradation of E2F-1 (Kontaki and Talianidis, 2010). Methylation of E2F-1 is reduced upon DNA damage, where the demethylation event is likely to be mediated by the lysine-specific demethylase, LSD1, which reinstates E2F-1 apoptotic activity (Kontaki and Talianidis, 2010).…”

“…There appears to be considerable interplay between methylation and other post-translational modifications; for example, methylation of E2F-1 antagonizes the acetylation and phosphorylation events that are required for its stabilization during the damage response, and methylation triggers ubiquitination and subsequent degradation of E2F-1 (Kontaki and Talianidis, 2010). Methylation of E2F-1 is reduced upon DNA damage, where the demethylation event is likely to be mediated by the lysine-specific demethylase, LSD1, which reinstates E2F-1 apoptotic activity (Kontaki and Talianidis, 2010). Given the interplay with ubiquitination, it is possible that methylation of E2F-1 acts as a pivotal mechanism to maintain E2F-1 levels at an appropriate level for normal cell cycle progression.…”

pVHL acts as a downstream target of E2F1 to suppress E2F1 activity

“…In response to various DNA-damage conditions, including ionizing radiation, UV radiation and chemotherapeutic drugs, E2F1 is induced and activated, resulting in expression of its downstream genes for induction of cell apoptosis [18,19]. Notably, upon DNA damage, E2F1 undergoes post-translational modifications, including phosphorylation, acetylation and deacetylation, resulting in modulation of its transactivation [20][21][22][23]. Given the multiple functions of E2F1, the role of E2F1 in tumour initiation and progression is relatively complicated, and E2F1 can exhibit either a tumour suppressive function or an oncogenic function.…”