Genomic Instability in Laminopathy-based Premature Aging

Abstract

Premature aging syndromes often result from mutations in nuclear proteins involved in the maintenance of genomic integrity. LAMIN A is a major component of the nuclear lamina and nuclear skeleton. Truncation in LAMIN A causes Hutchinson-Gilford Progerial Syndrome (HGPS), a severe form of early onset premature aging. Lack of functional ZMPSTE24, a metalloproteinase responsible for the maturation of Prelamin A, also results in progeroid phenotypes in mice and humans. To understand the molecular mechanism underlying HGPS, we investigated DNA damage and repair in mice lacking Zmpste24 and in cells from patients with HGPS. We found that Zmpste24-deficient mouse embryonic fibroblasts (MEFs) exhibit increased DNA damage and chromosome aberrations and are more sensitive to DNA-damaging agents. Bone marrow cells isolated from Zmpste24- /- mice display increased aneuploidy and the mice are more sensitive to DNA damaging agents. Recruitment of p53 binding protein 1 (53BP1) and Rad51 to sites of DNA lesions is impaired in Zmpste24-/- MEFs and in HGPS fibroblasts, resulting in delayed checkpoint response and defective DNA repair. Wild-type MEFs ectopically expressing unprocessible Prelamin A exhibit similar defects in checkpoint response and DNA repair. Our results indicate that unprocessed Prelamin A and truncated LAMIN A act dominant negatively to perturb the DNA-damage response and repair, resulting in genomic instability which might contribute to laminopathy-based premature aging