PT  - JOURNAL ARTICLE
AU  - Marjorie Fournier
AU  - Jean-Yves Bleuyard
AU  - Anthony M. Couturier
AU  - Jessica Ellins
AU  - Svenja Hester
AU  - Stephen J. Smerdon
AU  - László Tora
AU  - Fumiko Esashi
TI  - KAT2-mediated acetylation switches the mode of PALB2 chromatin association to safeguard genome integrity
AID  - 10.1101/735811
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 735811
4099  - http://biorxiv.org/content/early/2020/01/21/735811.short
4100  - http://biorxiv.org/content/early/2020/01/21/735811.full
AB  - 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.