KAT2-mediated acetylation switches the mode of PALB2 chromatin association to safeguard genome integrity

The tumour suppressor PALB2 stimulates RAD51-mediated homologous recombination (HR) repair of DNA damage, whilst its steady-state association with active genes protects these loci from replication stress. Here, we report that the lysine acetyltransferases 2A and 2B (KAT2A/2B, also called GCN5/PCAF), two well-known transcriptional regulators, acetylate a cluster of seven lysine residues (7K-patch) within the PALB2 chromatin association motif (ChAM) and, in this way, regulate context-dependent PALB2 binding to chromatin. In unperturbed cells, the 7K-patch is targeted for KAT2A/2B-mediated acetylation, which in turn enhances the direct association of PALB2 with nucleosomes. Importantly, DNA damage triggers a rapid deacetylation of ChAM and increases the overall mobility of PALB2. Distinct missense mutations of the 7K-patch render the mode of PALB2 chromatin binding, making it either unstably chromatin-bound (7Q) or randomly bound with a reduced capacity for mobilisation (7R). Significantly, both of these mutations confer a deficiency in RAD51 foci formation and increase DNA damage in S phase, leading to the reduction of overall cell survival. Thus, our study reveals that acetylation of the ChAM 7K-patch acts as a molecular switch to enable dynamic PALB2 shuttling for HR repair while protecting active genes during DNA replication.

Automated summary

The tumour suppressor PALB2 stimulates homologous recombination (HR) repair of DNA damage and protects active genes during DNA replication. Acetylation of the 7K-patch within the PALB2 chromatin association motif (ChAM) by KAT2A/2B enhances PALB2's association with nucleosomes. DNA damage triggers deacetylation of ChAM and increases PALB2's mobility. Mutations in the 7K-patch affect PALB2's chromatin binding, leading to defects in RAD51 foci formation and decreased cell survival.