DNA damage-induced replication stress results in PA200-proteasome-mediated degradation of acetylated histones

Imke K. Mandemaker, Marit E. Geijer, Iris Kik, Karel Bezstarosti, Erikjan Rijkers, Anja Raams, Roel C. Janssens, Hannes Lans, Jan H.J. Hoeijmakers, Jeroen A.A. Demmers, Wim Vermeulen, Jurgen A. Marteijn

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

38 Citaten (Scopus)

Samenvatting

Histone acetylation influences protein interactions and chromatin accessibility and plays an important role in the regulation of transcription, replication, and DNA repair. Conversely, DNA damage affects these crucial cellular processes and induces changes in histone acetylation. However, a comprehensive overview of the effects of DNA damage on the histone acetylation landscape is currently lacking. To quantify changes in histone acetylation, we developed an unbiased quantitative mass spectrometry analysis on affinity-purified acetylated histone peptides, generated by differential parallel proteolysis. We identify a large number of histone acetylation sites and observe an overall reduction of acetylated histone residues in response to DNA damage, indicative of a histone-wide loss of acetyl modifications. This decrease is mainly caused by DNA damage-induced replication stress coupled to specific proteasome-dependent loss of acetylated histones. Strikingly, this degradation of acetylated histones is independent of ubiquitylation but requires the PA200-proteasome activator, a complex that specifically targets acetylated histones for degradation. The uncovered replication stress-induced degradation of acetylated histones represents an important chromatin-modifying response to cope with replication stress.

Originele taal-2Engels
Artikelnummere45566
TijdschriftEMBO Reports
Volume19
Nummer van het tijdschrift10
DOI's
StatusGepubliceerd - okt. 2018

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