DNA repair complex licenses acetylation of H2A.Z.1 by KAT2A during transcription


Post-translational modifications of histone variant H2A.Z accompany gene transactivation, but its modifying enzymes still remain elusive. Here, we reveal a hitherto unknown function of human KAT2A (GCN5) as a histone acetyltransferase (HAT) of H2A.Z at the promoters of a set of transactivated genes. Expression of these genes also depends on the DNA repair complex XPC–RAD23–CEN2. We established that XPC–RAD23–CEN2 interacts both with H2A.Z and KAT2A to drive the recruitment of the HAT at promoters and license H2A.Z acetylation. KAT2A selectively acetylates H2A.Z.1 versus H2A.Z.2 in vitro on several well-defined lysines and we unveiled that alanine-14 in H2A.Z.2 is responsible for inhibiting the activity of KAT2A. Notably, the use of a nonacetylable H2A.Z.1 mutant shows that H2A.Z.1ac recruits the epigenetic reader BRD2 to promote RNA polymerase II recruitment. Our studies identify KAT2A as an H2A.Z.1 HAT in mammals and implicate XPC–RAD23–CEN2 as a transcriptional co-activator licensing the reshaping of the promoter epigenetic landscape.

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Fig. 1: XPC–RAD23–CEN2 interacts with histone variant H2A.Z.
Fig. 2: XPC–RAD23–CEN2 triggers deposition of H2A.Zac at transactivated promoters.
Fig. 3: KAT2A is involved in the deposition of H2A.Zac at transactivated promoters.
Fig. 4: KAT2A acetylates H2A.Z.1 versus H2A.Z.2 in vitro.
Fig. 5: Acetylation of H2A.Z.1 is required for XPC-dependent gene transactivation.
Fig. 6: BRD2 is a co-activator for XPC-positively regulated gene expression.

Data availability

Data are available on SRA repository under accession number PRJNA517640. Further information and requests for resources and reagents should be directed to the lead contact, F.C. (fredr@igbmc.fr).


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We are grateful to A. Hamiche, L. Tora and A. Poterszman (IGBMC, France) for expression vectors and antibodies, to K. Sugasawa (Kobe University, Japan) for the antibodies against CEN2 and to members of our team. We thank L. Tora for critical reading and IGBMC antibody and cell culture facilities. This study was supported by the INCA (2017-11537), the ligue contre le cancer (Equipe labélisée 2019, FC) and the ANR-10-LABX-0030-INRT, a French State fund managed by the Agence Nationale de la Recherche under the frame program Investissements d’Avenir ANR-10-IDEX-0002-02. M.S was supported by ‘le prix d’encouragement à la recherche de la province Sud (New Caledonia)’. G.C. was supported by a PhD fellowship (2214-A) from the Scientific and Technological Research Council of Turkey (TÜBİTAK). Sequencing was performed by the IGBMC Microarray and Sequencing platform, a member of the ‘France Génomique’ consortium (ANR-10-INBS-0009). Note that part of the text in this article may overlap with the published thesis by M. Semer.

Author information




M.S. performed mass spectrometry, RT–PCR and western blot assay determining the interaction between XPC and H2A.Z. B.B. performed the bioinformatics work of ChIP data. G.C. expressed and purified the recombinant human HAT module of the ATAC complex and the catalytically dead KAT2A mutant. A.L. and P.C. performed site-directed mutagenesis and HAT assays. N.L.M. performed ChIP-seq and HAT assays. J.M.E. analyzed results. F.C. and N.L.M. conceived the experiments and supervised the work. F.C. wrote the manuscript with input from N.L.M.

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Correspondence to F. Coin or N. Le May.

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Supplementary Information

Supplementary Figures 1–35, Supplementary Tables 1–3 and title/legend for Supplementary Dataset 1

Reporting Summary

Supplementary Dataset 1

List of genes co-occupied by XPC and RNAPII.

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Semer, M., Bidon, B., Larnicol, A. et al. DNA repair complex licenses acetylation of H2A.Z.1 by KAT2A during transcription. Nat Chem Biol 15, 992–1000 (2019). https://doi.org/10.1038/s41589-019-0354-y

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