Departament de Biologia Cel·lular, Fisiologia i Immunologia, Facultat de Biociències, Universitat Autònoma de Barcelona, Bellaterra, Spain.
Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Spain.
Biogerontology. 2022 Aug;23(4):499-514. doi: 10.1007/s10522-022-09979-6. Epub 2022 Jul 18.
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.
随着年龄的增长，DNA 双链断裂（DSB）的频率增加，这表明 DSB 修复效率随年龄的增长而下降，而 DSB 修复效率也受到表观遗传景观的影响。组蛋白 H4 在赖氨酸 16 位的乙酰化（H4K16Ac）与 DSB 修复有关，因为该标记的去乙酰化对于 53BP1 有效地募集到 DSB 是必需的。尽管已经研究了 H4K16Ac 水平随年龄的变化，但它们对与年龄相关的 DSB 积累的贡献仍不清楚。在体外，衰老的人真皮成纤维细胞（HDF）显示出较低水平的 H4K16Ac，这与 53BP1 募集到基础 DSB 的减少有关。在 DNA 损伤诱导后，早期传代（EP）细胞经历短暂的 H4K16 去乙酰化，从而允许 53BP1 适当募集到 DSB。相比之下，为了达到这个特定的最佳水平，衰老的细胞通过增加它们整体较低的 H4K16Ac 水平来做出反应。使用 Trichostatin A 诱导晚期传代（LP）细胞的超乙酰化增加了 H4K16Ac 水平，但并没有改善 53BP1 的募集。相反，沉默 MOF 诱导的去乙酰化降低了 EP 和 LP 细胞中 H4K16Ac 水平，并损害了 53BP1 的募集。与年龄相关的 H4K16Ac 水平的降低导致了体外衰老细胞显示的修复缺陷。H4K16Ac 对 DNA 损伤做出反应，以达到允许适当 53BP1 募集的特定的最佳水平。这种反应可能会随着年龄的增长而受到损害，因为 LP 细胞的 H4K16Ac 水平较低。在 DNA 损伤反应的激活和衰老过程中 H4K16Ac 的变化表明，这种组蛋白标记是 DNA 修复和与年龄相关的染色质改变之间的关键介质。
