Nuclear lamin A in chromatin remodeling, DNA damage repair and aging

Abstract

Abnormal splicing of LMNA gene gives rise to a truncated prelamin A termed as progerin which is accumulated in patients suffering from Hutchinson-Gilford progeria Syndrome. Lamin A interacts with and activates a variety of nuclear factors including histone modifying enzymes such as MOF, SUV39H1, SIRT1 and SIRT6. The presence of progerin compromises the proper association of these important nuclear proteins with nuclear matrix, leading to defective chromatin remodeling in response to DNA damage. The nuclear lamin A also serves as activators for SIRT1 and SIRT6 that are critical in stem cell maintenance and DNA damage repair. Targeting the epigenetic changes significantly rescue the cellular senescence and extend lifespan in progeroid mice. Our studies suggest a profound role for lamin A in regulating nuclear architecture, chromatin dynamics and stem cell potency that all contribute to the aging processes.