Molecular dynamics simulations reveal how H3K56 acetylation impacts nucleosome structure to promote DNA exposure for lesion sensing

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The first order of DNA packaging is the nucleosome with the DNA wrapped around the histone octamer. This leaves the nucleosomal DNA with access restrictions, which impose a significant barrier to repair of damaged DNA. The efficiency of DNA repair has been related to nucleosome structure and chromatin status, which is modulated in part by post-translational modifications (PTMs) of histones. Numerous studies have suggested a role for acetylation of lysine at position 56 of the H3 histone (H3K56ac) in various DNA transactions, including the response to DNA damage and its association with human cancer. Biophysical studies have revealed that H3K56ac increases DNA accessibility by facilitating spontaneous and transient unwrapping motions of the DNA ends. However, how this acetylation mark modulates nucleosome structure and dynamics to promote accessibility to the damaged DNA for repair factors and other proteins is still poorly understood. Here, we utilize approximately 5–6 microseconds of atomistic molecular dynamics simulations to delineate the impact of H3K56 acetylation on the nucleosome structure and dynamics, and to elucidate how these nucleosome properties are further impacted when a bulky benzo[a]pyrene-derived DNA lesion is placed near the acetylation site. Our findings reveal that H3K56ac alone induces considerable disturbance to the histone-DNA/histone-histone interactions, and amplifies the distortions imposed by the presence of the lesion. Our work highlights the important role of H3K56 acetylation in response to DNA damage and depicts how access to DNA lesions by the repair machinery can be facilitated within the nucleosome via a key acetylation event.

Original languageEnglish (US)
Article number103201
JournalDNA Repair
StatePublished - Nov 2021


  • DNA unwrapping
  • DNA- benzo[a]pyrenyl adduct
  • H3K56 acetylation
  • Molecular dynamics simulations
  • Nucleosome core particle
  • Nucleotide excision repair
  • Posttranslational modification

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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