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

Marjorie Fournier (1) , Jean-Yves Bleuyard (1) , Anthony Couturier (2) , Jessica Ellins (1) , Svenja Hester (1) , Stephen Smerdon (3) , Làszlo Tora (4) , Fumiko Esashi (1)

1 Sir William Dunn School of Pathology [Oxford]
2 Sir William Dunn School of Pathology [Oxford]
3 The Francis Crick Institute [London]
4 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire

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.

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.

Domaines: Sciences du Vivant [q-bio]

Marjorie Fournier, Jean-Yves Bleuyard, Anthony Couturier, Jessica Ellins, Svenja Hester, et al.. KAT2-mediated acetylation switches the mode of PALB2 chromatin association to safeguard genome integrity. 2020. ⟨hal-02992877⟩