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bioRxiv · 10.1101/735811

Lysine acetylation promotes PALB2 chromatin association to maintain genome stability

Esashi, F.·Fournier, M.·Bleuyard, J.-Y.·Couturier, A. M.·Ellins, J.·Hester, S.·Smerdon, S. J.·Tora, L.
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Abstract

The tumour suppressor PALB2 stimulates error-free repair of DNA breaks, whilst its steady-state chromatin association protects active genes from genotoxic stress. Here, we report that the lysine acetyltransferases 2A and 2B (KAT2A/B), commonly known to promote transcriptional activation, acetylate the PALB2 chromatin association motif (ChAM), providing a dynamic regulatory mechanism for PALB2. ChAM acetylation within a cluster of seven lysine residues (7K), detected in the chromatin-enriched fraction in undamaged cells, enhanced its association with nucleosomes while decreasing its non-specific binding to naked DNA. DNA damage triggered a rapid deacetylation of ChAM and a concomitant increase in PALB2 mobility. Significantly, a 7K-null mutation, which hindered ChAM binding to both nucleosomes and DNA, conferred deficiency in DNA repair and hypersensitivity to the anti-cancer drug olaparib. Thus, our study reveals a unique mechanism mediated by KAT2A/B-dependent acetylation of a non-histone protein, which fine-tunes the DNA damage response and hence promotes genome stability.

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Esashi, F., Fournier, M., Bleuyard, J.-Y., Couturier, A. M., Ellins, J., Hester, S., Smerdon, S. J., Tora, L.. 2019-08-15. Lysine acetylation promotes PALB2 chromatin association to maintain genome stability. https://doi.org/10.1101/735811

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