Research Perspective Volume 3, Issue 10 pp 943—954

‘Relax and Repair’ to restrain aging


Figure 2. Model showing the relationship between impaired histone acetylation, defective DSB repair and pre-mature aging. H4K16 acetylation impedes the ability of chromatin to form cross-fibre interactions and this converts chromatin into a ‘relaxed’ conformation. Mof, a MYST family histone acetyltransferase, is the enzyme mainly involved in acetylation of H4 at K16 position in mammalian cells. The 18 amino acid C-terminal tail of prelamin A prevents the proper association of Mof to the nuclear matrix leading to Mof mislocalization and the hypoacetylation of histone H4K16. Defective H4K16 acetylation, in turn, results in global chromatin compaction and the inability to assume the chromatin conformation required for repair process access. Consequently, the delayed recruitment of repair proteins to sites of DSBs causes the accumulation of irreparable DNA damage, chronic DNA damage response, early cellular senescence and premature aging.