Journal
MOLECULAR CELL
Volume 62, Issue 3, Pages 409-421Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2016.03.031
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Funding
- Canadian Institutes of Health Research (CIHR) [MOP-123322, FDN-143343, FDN-143314]
- Natural Sciences and Engineering Research Council of Canada [RGPIN-2014-059680]
- European Research Council [ERC-2014-CoG 647344]
- Agence Nationale pour la Recherche [ANR-14-CE10-0002-01, ANR-13-BSV8-0013]
- Ligue Nationale contre le Cancer
- NIH [CA129537, CA154320, GM109768]
- Quebec Breast Cancer Foundation
- Fonds Quebecois de la Recherche sur la Nature et les Technologies
- CIHR
- TD Bank Health Research Fellowship at the Lunenfeld-Tanenbaum Research Institute
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The NuA4/TIP60 acetyltransferase complex is a key regulator of genome expression and stability. Here we identified MBTD1 as a stable subunit of the complex, and we reveal that, via a histone reader domain for H4K20me1/2, MBTD1 allows TIP60 to associate with specific gene promoters and to promote the repair of DNA double-strand breaks by homologous recombination. It was previously suggested that TIP60-dependent acetylation of H4 regulates binding of the non-homologous end joining factor 53BP1, which engages chromatin through simultaneous binding of H4K20me2 and H2AK15ub. We find that the TIP60 complex regulates association of 53BP1 partly by competing for H4K20me2 and by regulating H2AK15ub. Ubiquitylation of H2AK15 by RNF168 inhibits chromatin acetylation by TIP60, while this residue can be acetylated by TIP60 in vivo, blocking its ubiquitylation. Altogether, these results uncover an intricate mechanism orchestrated by the TIP60 complex to regulate 53BP1-dependent repair through competitive bivalent binding and modification of chromatin.
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