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Kiss, A.E.* ; Venkatasubramani, A.V.* ; Pathirana, D.* ; Krause, S.* ; Sparr, A.C.* ; Hasenauer, J. ; Imhof, A.* ; Müller, M.* ; Becker, P.B.*

Processivity and specificity of histone acetylation by the male-specific lethal complex.

Nucleic Acids Res. 52, 4889-4905 (2024)
DOI PMC
Creative Commons Lizenzvertrag
Open Access Gold möglich sobald Verlagsversion bei der ZB eingereicht worden ist.
Acetylation of lysine 16 of histone H4 (H4K16ac) stands out among the histone modifications, because it decompacts the chromatin fiber. The metazoan acetyltransferase MOF (KAT8) regulates transcription through H4K16 acetylation. Antibody-based studies had yielded inconclusive results about the selectivity of MOF to acetylate the H4 N-terminus. We used targeted mass spectrometry to examine the activity of MOF in the male-specific lethal core (4-MSL) complex on nucleosome array substrates. This complex is part of the Dosage Compensation Complex (DCC) that activates X-chromosomal genes in male Drosophila. During short reaction times, MOF acetylated H4K16 efficiently and with excellent selectivity. Upon longer incubation, the enzyme progressively acetylated lysines 12, 8 and 5, leading to a mixture of oligo-acetylated H4. Mathematical modeling suggests that MOF recognizes and acetylates H4K16 with high selectivity, but remains substrate-bound and continues to acetylate more N-terminal H4 lysines in a processive manner. The 4-MSL complex lacks non-coding roX RNA, a critical component of the DCC. Remarkably, addition of RNA to the reaction non-specifically suppressed H4 oligo-acetylation in favor of specific H4K16 acetylation. Because RNA destabilizes the MSL-nucleosome interaction in vitro we speculate that RNA accelerates enzyme-substrate turn-over in vivo, thus limiting the processivity of MOF, thereby increasing specific H4K16 acetylation.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Nucleosome Core Particle; In-vitro Reconstitution; Dosage Compensation; X-chromosome; Functional-integration; Quantitative-analysis; H4-k16 Acetylation; Mass-spectrometry; Rox Rnas; Chromatin
ISSN (print) / ISBN 0305-1048
e-ISSN 1362-4962
Quellenangaben Band: 52, Heft: 9, Seiten: 4889-4905 Artikelnummer: , Supplement: ,
Verlag Oxford University Press
Verlagsort Great Clarendon St, Oxford Ox2 6dp, England
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Förderungen DFG
German Research Council (DFG)