Poly ADP-ribosylation of SET8 leads to aberrant H4K20 methylation in mammalian nuclear genome

Abstract

In mammalian cells, SET8 mediated Histone H4 Lys 20 monomethylation (H4K20me1) has been implicated in regulating mitotic condensation, DNA replication, DNA damage response, and gene expression. Here we show SET8, the only known enzyme for H4K20me1 is post-translationally poly ADP-ribosylated by PARP1 on lysine residues. PARP1 interacts with SET8 in a cell cycle- dependent manner. Poly ADP-ribosylation on SET8 renders it catalytically compromised and it undergoes degradation via ubiquitylation pathway. Knockdown of PARP1 shifted the relative dynamic equilibrium of H4K20me2 to H4k20me3 in cells. Overexpression or knockdown of PARP1 led to aberrant H4K20me1 domains genome-wide, impacting Wnt signaling pathways genes and transcription factor binding site enrichment. Therefore, SET8 mediated chromatin remodeling and gene expression in mammalian cells are influenced by poly ADP-ribosylation by PARP1.

Mono-methylated histones control PARP-1 in chromatin and transcription

“…S4-5), indicating that PARP-1 is not directly implicated in the regulation of pr-set7. This finding contrasts with recent evidence demonstrating PARP1-induced degradation of PR-SET7/SET8 in human cells (16).…”

“…A recent study demonstrated that in human cells overexpressing PARP-1, PR-SET7/SET8 is degraded, whereas depletion of PARP-1 leads to an increase in PR-SET7/SET8 levels (16).…”

“…Each of these histone modifications can interchangeably facilitate this function. The spreading of PARP-1 to the gene body contributes to the loosening of chromatin in this region(7,16, 17,49). Consequently, this facilitates the transition of Pol II into a productive elongation phase, leading to the generation of a mature transcript.…”