DNA repair defects and genome instability in Hutchinson-Gilford Progeria Syndrome

Abstract

The integrity of the nuclear lamina has emerged as an important factor in the maintenance of genome stability. In particular, mutations in the LMNA gene, encoding A-type lamins (lamin A/C), alter nuclear morphology and function, and cause genomic instability. LMNA gene mutations are associated with a variety of degenerative diseases and devastating premature aging syndromes such as Hutchinson-Gilford Progeria Syndrome (HGPS) and Restrictive Dermopathy (RD). HGPS is a severe laminopathy, with patients dying in their teens from myocardial infarction or stroke. HGPS patient-derived cells exhibit nuclear shape abnormalities, changes in epigenetic regulation and gene expression, telomere shortening, genome instability, and premature senescence. This review highlights recent advances in identifying molecular mechanisms that contribute to the pathophysiology of HGPS, with a special emphasis on DNA repair defects and genome instability.

Figure 1. Genome instability in progeria cells

In normal cells, dispersed networks of A-type lamin filaments support the inner nuclear membrane (INM) and extend throughout the nucleoplasm. Chromosomes have long and functional telomeres, normal levels of histone modifications, and can recruit DNA repair factors to DNA double-strand breaks. By contrast progerin accumulates at the inner nuclear membrane and eventually recruits normal lamins, collapsing their networks. Progeria cells suffer telomere shortening and deficient recruitment of factors needed for homologous repair (HR) and non-homologous end joining (NHEJ) mechanisms of repair. This leads to the accumulation of phosphorylated H2AX (γH2AX, indicated by yellow ‘P’), a marker of unrepaired DNA damage. Progeria cells accumulate ROS, which damages DNA, and misregulation of histone modifications (Ac, acetylation; Me, methylation; Ub, ubiquitinylation) also contributes to genomic instability.

Figure 1. Genome instability in progeria cells

In normal cells, dispersed networks of A-type lamin filaments support the inner nuclear membrane (INM) and extend throughout the nucleoplasm. Chromosomes have long and functional telomeres, normal levels of histone modifications, and can recruit DNA repair factors to DNA double-strand breaks. By contrast progerin accumulates at the inner nuclear membrane and eventually recruits normal lamins, collapsing their networks. Progeria cells suffer telomere shortening and deficient recruitment of factors needed for homologous repair (HR) and non-homologous end joining (NHEJ) mechanisms of repair. This leads to the accumulation of phosphorylated H2AX (γH2AX, indicated by yellow ‘P’), a marker of unrepaired DNA damage. Progeria cells accumulate ROS, which damages DNA, and misregulation of histone modifications (Ac, acetylation; Me, methylation; Ub, ubiquitinylation) also contributes to genomic instability.