Defective DNA-damage repair induced by nuclear lamina dysfunction is a key mediator of smooth muscle cell aging

Abstract

Accumulation of DNA damage is a major driving force of normal cellular aging and has recently been demonstrated to hasten the development of vascular diseases such as atherosclerosis. VSMCs (vascular smooth muscle cells) are essential for vessel wall integrity and repair, and maintenance of their proliferative capacity is essential for vascular health. The signalling pathways that determine VSMC aging remain poorly defined; however, recent evidence implicates persistent DNA damage and the A-type nuclear lamins as key regulators of this process. In the present review, we discuss the importance of the nuclear lamina in the spatial organization of nuclear signalling events, including the DNA-damage response. In particular, we focus on the evidence suggesting that prelamin A accumulation interferes with nuclear spatial compartmentalization by disrupting chromatin organization and DNA-damage repair pathways to promote VSMC aging and senescence.

Lamins at a glance

“…DNA repair proteins such as breast cancer type 1 susceptibility protein (BRCA1) and RAD51 are transcriptionally downregulated by pRband E2F4-mediated pathways Manju et al, 2006;Musich and Zou, 2009;Redwood et al, 2011). Detailed reviews of lamins and DNA repair have been published (Gonzalez-Suarez et al, 2009a;Warren and Shanahan, 2011).…”

Oxydative stress alters nuclear shape through lamins dysregulation

“…The increase of protein level could even counteract or outweigh the decrease of gene expression, in case of important or persistent oxidative stress (as review 12 ). In contrast with silencing of lamin A, after the silencing of lamin B1, no γ-H2AX foci were observed, although an increase in ATM, Chk1 and Chk2 were detected.…”

“…Additionally, other roles for lamina in the control of mitosis, DNA replication or the DNA damage response have more recently emerged. 11,12 Progeroid syndromes have often been classified into two categories: laminopathies, such as HGPS, which are associated Lamin A is synthesized as a precursor molecule (prelamin A), which is then post-translationally modified to generate mature lamin A lacking the carboxylterminal tail. The steps of the maturation are as follows: prelamin A is first modified by a farnesyltransferase.…”

Nuclear Envelope Disease and Chromatin Organization

“…Progeroid patients display aged VSMCs (vascular smooth muscle cells) similar to those in normal old people. Thus incorrectly processed prelamin A contributes towards the molecular perturbations associated with several progeroid and lipodystrophy syndromes, as well as being a marker for normal VSMC aging [9].…”