Abstract
SUMMARY Although the inverse affinities of 53BP1 and BRCA1-BARD1 complexes for distinct methylation sates 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 primordial for the onset of the recombinogenic functions of BRCA1 during unperturbed DNA replication. Indeed, independently of other H4K20me states, we determined that the SET8-induced switch from un-methyl to mono-methyl H4K20 followed by the activation of the ubiquitin ligase RNF168 constitutes a turn-off signal of homologous recombination by tipping the balance from BRCA1-BARD1 to 53BP1 complexes on post-replicated chromatin. Conversely, the lack of SET8 and the absence of H4K20 monomethylation after DNA replication led to an inaccurate 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 the activity of SET8 on chromatin as the primary inhibitory lock of BRCA1-mediated HR pathway during the cell cycle.