Oxydative stress alters nuclear shape through lamins dysregulation: a route to senescence

Abstract

Progeroid phenotypes are mainly encountered in 2 types of syndromes: in laminopathies, which are characterized by nuclear shape abnormalities due to lamin A alteration, and in DNA damage response defect syndromes. Because lamin A dysregulation leads to DNA damages, it has been proposed that senescence occurs in both types of syndromes through the accumulation of damages. We recently showed that elevated oxidative stress is responsible for lamin B1 accumulation, nuclear shape alteration and senescence in the DDR syndrome, ataxia telangiectasia (A-T). Interestingly, overexpression of lamin B1 in wild type cells is sufficient to induce senescence without the induction of DNA damages. Here, we will discuss the importance of controlling the lamins level in order for maintenance nuclear architecture and we will comment the relationships of lamins with other senescence mechanisms. Finally, we will describe emerging data reporting redox control by lamins, leading us to propose a general mechanism by which reactive oxygen species can induce senescence through lamin dysregulation and NSA.

Figure 1. Interplay between oxidative stress, telomere shortening, and DNA damage for the induction of senescence. Oxidative stress, regardless of the cause, is known to alter telomeres and to cause DNA damage. Telomere shortening and DNA damage are involved in the induction of senescence. Our group and others have reported that oxidative stress can alter lamins functions (by oxidation of lamin A, accumulation of pre-lamin A or lamin B1) leading to nuclear shape. All these alterations are associated with senescence. Interestingly, dysregulation of lamins is also associated with telomere shortening and DNA damage.

Figure 2. Consequences of oxidative stress through lamins dyregulation. An elevated ROS level has been observed after genotoxic stress, oncogene activation, or deficiency of ATM. We found that in ataxia telangiectasia, the elevated ROS leads to an accumulation of lamin B1 by p38 MAPK activation. This accumulation leads to nuclear shape alteration and senescence. Interestingly, it has been proposed that the duplication of lamin B1 is responsible for demyelination of centraln nervous system in adult-onset autosomal dominant leukodystrohy (ADLD) and might potentially explain other neurological defects. Redox regulation is altered in Hutchinson-Gilford progeria cells or in lamin B1-deficient cells. Oxidative stress affects the function of lamin A by oxidation. Altered levels of lamin accumulation and defects in lamins cause alterations in nuclear shape and lead to senescence. Lamin A dysregulation affects DNA damage signaling and repair, leading to genetic instability. This genetic instability can partially participate in premature aging and may also cause the tumoral predisposition observed in DDR pathies. However, in laminopathies, no cancer predisposition is observed, suggesting in this case that senescence hampers the proliferation of cells harbouring DNA damage.