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

Abstract

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.

ATAC and SAGA co-activator complexes utilize co-translational assembly, but their cellular localization properties and functions are distinct

“… 7 , 8 , 19 – 22 Importantly, besides histone proteins, KAT2A/KAT2B also acetylate non-histone targets, such as p53, E2F1, c-MYC, PLK4, or PALB2. 23 – 34 …”

ATAC and SAGA coactivator complexes utilize co-translational assembly, but their cellular localization properties and functions are distinct

“…7,8,[19][20][21][22] Importantly, besides histone proteins, KAT2A/KAT2B also acetylate non-histone targets, such as p53, E2F1, c-MYC, PLK4, or PALB2. [23][24][25][26][27][28][29][30][31][32][33][34] In spite of the related HAT activities of ATAC and SAGA, differences in subunit composition between the two distinct complexes suggested that they play different regulatory roles in transcription regulation and/or cellular homeostasis. 8,29,32,[35][36][37][38][39] Also, it has been shown that by regulating transcription through HAT-independent pathways, ATAC and SAGA are differentially required for self-renewal of mouse embryonic stem cells (mESCs).…”