The functional antagonism between SIRT2 and MOF regulates cell cycle progression and genome stability [ChIP-seq]

The control of G2/M transition is a key event for genome stability as it ensures proper completion of DNA replication and repair before progressing into mitosis. One of the key regulators of G2/M checkpoint is the H4K16Ac-acetyltransferase MOF, which plays a major role in chromatin structure, gene expression, DNA damage and genome stability. Here we show that SIRT2, a member of the sirtuin family of NAD+-dependent deacetylases, antagonizes the role of MOF in G2/M. SIRT2 promotes specific inactivation of MOF through deacetylation and degradation of MOF, which results in re-expression of G2/M cell-cycle genes regulated by MOF. Underscoring the functional relevance of this antagonism, both factors play opposed roles in the deposition of the key mark H4K20me1 during G2/M. Consistently, loss of MOF in wt but not in SIRT2-/- cells induces a genome-wide deregulation of H4K20me1 distribution, which results in a premature loading of condensins. Our studies suggest that the G2/M checkpoint is shaped by the balance between both factors and involves condensing regulation and underscores the role of sirtuins in cell cycle control and genome stability under stress.