Histone H3 lysine 56 acetylation and the response to DNA replication fork damage.
In Saccharomyces cerevisiae, histone H3 lysine 56 acetylation (H3K56ac) occurs in newly synthesized histones that are deposited throughout the genome during DNA replication. Defects in H3K56ac sensitize cells to genotoxic agents, suggesting that this modification plays an important role in the DNA damage response. However, the links between histone acetylation, the nascent chromatin structure, and the DNA damage response are poorly understood. Here we report that cells devoid of H3K56ac are sensitive to DNA damage sustained during transient exposure to methyl methanesulfonate (MMS) or camptothecin but are only mildly affected by hydroxyurea. We demonstrate that, after exposure to MMS, H3K56ac-deficient cells cannot complete DNA replication and eventually segregate chromosomes with intranuclear foci containing the recombination protein Rad52. In addition, we provide evidence that these phenotypes are not due to defects in base excision repair, defects in DNA damage tolerance, or a lack of Rad51 loading at sites of DNA damage. Our results argue that the acute sensitivity of H3K56ac-deficient cells to MMS and camptothecin stems from a failure to complete the repair of specific types of DNA lesions by recombination and/or from defects in the completion of DNA replication.
Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada.
Hugo
H
Wurtele
Gitte Schalck
GS
Kaiser
Julien
J
Bacal
Edlie
E
St-Hilaire
Eun-Hye
EH
Lee
Sarah
S
Tsao
Jonas
J
Dorn
Paul
P
Maddox
Michael
M
Lisby
Philippe
P
Pasero
Alain
A
Verreault
D000107:Acetylation; D000970:Antineoplastic Agents / Q000494:pharmacology; D002166:Camptothecin / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair; D004261:DNA Replication / Q000187:drug effects; D004271:DNA, Fungal / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006918:Hydroxyurea / Q000494:pharmacology; D008239:Lysine / Q000235:genetics / Q000378:metabolism*; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D009153:Mutagens / Q000494:pharmacology; D009154:Mutation; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D004271:DNA, Fungal; D006657:Histones; D009153:Mutagens; D029701:Saccharomyces cerevisiae Proteins; D008741:Methyl Methanesulfonate; D008239:Lysine; D006918:Hydroxyurea; D002166:Camptothecin