Role of H4K16 acetylation in 53BP1 recruitment to double-strand break sites in in vitro aged cells

Lourdes González-Bermúdez, Anna Genescà, Mariona Terradas, Marta Martín*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

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Increased frequency of DNA double strand breaks (DSBs) with aging suggests an age-associated decline in DSB repair efficiency, which is also influenced by the epigenetic landscape. H4 acetylation at lysine 16 (H4K16Ac) has been related to DSB repair since deacetylation of this mark is required for efficient 53BP1 recruitment to DSBs. Although age-associated changes in H4K16Ac levels have been studied, their contribution to age-related DSB accumulation remains unknown. In vitro aged Human Dermal Fibroblasts (HDFs) display lower levels of H4K16A that correlate with reduced recruitment of 53BP1 to basal DSBs. Following DNA damage induction, early passage (EP) cells suffered from a transient H4K16 deacetylation that allowed proper 53BP1 recruitment to DSBs. In contrast, to reach this specific and optimum level, aged cells responded by increasing their overall lower H4K16Ac levels. Induced hyperacetylation of late passage (LP) cells using trichostatin A increased H4K16Ac levels but did not ameliorate 53BP1 recruitment. Instead, deacetylation induced by MOF silencing reduced H4K16Ac levels and compromised 53BP1 recruitment in both EP and LP cells. Age-associated decrease of H4K16Ac levels contributes to the repair defect displayed by in vitro aged cells. H4K16Ac responds to DNA damage in order to reach a specific, optimum level that allows proper 53BP1 recruitment. This response may be compromised with age, as LP cells depart from lower H4K16Ac levels. Variations in H4K16Ac following the activation of the DNA damage response and aging point at this histone mark as a key mediator between DNA repair and age-associated chromatin alterations.

Original languageEnglish
Pages (from-to)499-514
Number of pages16
Issue number4
Publication statusPublished - Aug 2022


  • 53BP1
  • Acetylation
  • Aged
  • CRB2
  • DNA Breaks, Double-Stranded
  • DNA Repair
  • DNA damage
  • Double strand break repair
  • H4 LYSINE-16
  • H4K16 acetylation
  • Histones/metabolism
  • Humans
  • In vitro aging
  • MOF
  • Protein Processing, Post-Translational


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