Cell-cycle dependent inhibition of BRCA1 signaling by the lysine methyltransferase SET8

Abstract

SUMMARYAlthough the inverse affinities of 53BP1 and BRCA1-BARD1 complexes for distinct methylation states of lysine (K) 20 at histone H4 have underscored a role of this epigenetic mark in the regulation of DNA-repair pathways choice, how the different H4K20 methyltransferases are involved remained unclear. Here, we show that the replication-coupled degradation of the lysine methyltransferase SET8 responsible for H4K20 mono-methylation (H4K20me1) is required for the onset of the recombinogenic functions of BRCA1 during unperturbed DNA replication. Indeed, we demonstrate that SET8 can work as a primary inhibitor of homologous recombination by tipping the balance from BRCA1-BARD1 to 53BP1 complexes in a manner depending on the single switch from un-methyl to mono-methyl H4K20 and the recruitment of the ubiquitin ligase RNF168 on post-replicated chromatin. Conversely, the lack of SET8 and K20 mono-methylation on newly assembly chromatin after DNA replication led to the untimely chromatin accumulation of BRCA1 at the exit of mitosis, which contributes to the improper progression from G1 to S-phase in daughter cells. Altogether, these results establish thede novoactivity of SET8 on chromatin as a primordial epigenetic lock of BRCA1-mediated HR pathway during the cell cycle.