Lysine acetylation promotes PALB2 chromatin association to maintain genome stability

The tumour suppressor PALB2 stimulates error-free DNA repair by homologous recombination (HR). It also associates with actively transcribed chromatin and protects these regions from DNA damage. However, the mechanism by which PALB2 switches between these functions remains enigmatic. Here, we show that the PALB2 chromatin association motif (ChAM), which directly binds to nucleosomes, is targeted by acetylation at a cluster of seven lysine residues (the 97K-patch9). ChAM acetylation within the 7K-patch enhances its nucleosome binding, while limiting its non-specific DNA binding. Importantly, ChAM acetylation is rapidly removed upon DNA damage, resulting in reduced PALB2 chromatin association and increased mobility within the nucleus. The 7K-null mutation confers HR deficiency, including increased sensitivity to the anti-cancer drug Olaparib. Thus, our findings reveal a unique mechanism mediated by acetylation of non-histone protein, which regulates the chromatin interaction of PALB2 to orchestrate efficient DNA repair in human cells and hence promotes genome stability.