Histone degradation in response to DNA damage enhances chromatin dynamics and recombination rates

TY - JOUR

T1 - Histone degradation in response to DNA damage enhances chromatin dynamics and recombination rates

AU - Hauer, Michael H.

AU - Seeber, Andrew

AU - Singh, Vijender

AU - Thierry, Raphael

AU - Sack, Ragna

AU - Amitai, Assaf

AU - Kryzhanovska, Mariya

AU - Eglinger, Jan

AU - Holcman, David

AU - Owen-Hughes, Tom

AU - Gasser, Susan M.

N1 - M.H.H. was supported by a PhD fellowship of the Boehringer Ingelheim Fonds. S.M.G. thanks the HFSP, SNSF and the Novartis Research Foundation for support.

PY - 2017/2

Y1 - 2017/2

N2 - Nucleosomes are essential for proper chromatin organization and the maintenance of genome integrity. Histones are post-translationally modified and often evicted at sites of DNA breaks, facilitating the recruitment of repair factors. Whether such chromatin changes are localized or genome-wide is debated. Here we show that cellular levels of histones drop 20-40% in response to DNA damage. This histone loss occurs from chromatin, is proteasome-mediated and requires both the DNA damage checkpoint and the INO80 nucleosome remodeler. We confirmed reductions in histone levels by stable isotope labeling of amino acids in cell culture (SILAC)-based mass spectrometry, genome-wide nucleosome mapping and fluorescence microscopy. Chromatin decompaction and increased fiber flexibility accompanied histone degradation, both in response to DNA damage and after artificial reduction of histone levels. As a result, recombination rates and DNA-repair focus turnover were enhanced. Thus, we propose that a generalized reduction in nucleosome occupancy is an integral part of the DNA damage response in yeast that provides mechanisms for enhanced chromatin mobility and homology search.

AB - Nucleosomes are essential for proper chromatin organization and the maintenance of genome integrity. Histones are post-translationally modified and often evicted at sites of DNA breaks, facilitating the recruitment of repair factors. Whether such chromatin changes are localized or genome-wide is debated. Here we show that cellular levels of histones drop 20-40% in response to DNA damage. This histone loss occurs from chromatin, is proteasome-mediated and requires both the DNA damage checkpoint and the INO80 nucleosome remodeler. We confirmed reductions in histone levels by stable isotope labeling of amino acids in cell culture (SILAC)-based mass spectrometry, genome-wide nucleosome mapping and fluorescence microscopy. Chromatin decompaction and increased fiber flexibility accompanied histone degradation, both in response to DNA damage and after artificial reduction of histone levels. As a result, recombination rates and DNA-repair focus turnover were enhanced. Thus, we propose that a generalized reduction in nucleosome occupancy is an integral part of the DNA damage response in yeast that provides mechanisms for enhanced chromatin mobility and homology search.

KW - Chromatin structure

KW - DNA damage response

KW - Genomic instability

KW - Mass spectrometry

KW - Microscopy

U2 - 10.1038/nsmb.3347

DO - 10.1038/nsmb.3347

M3 - Article

C2 - 28067915

SN - 1545-9993

VL - 24

SP - 99

EP - 107

JO - Nature Structural & Molecular Biology

JF - Nature Structural & Molecular Biology

IS - 2

ER -