Role of Lamin A in Maintaining Genome Stability and Nuclear Organization of Cancer Cells

Abstract

Lamins are structural proteins of the inner nuclear membrane essential for maintaining nuclear structure and function. In order to study the role of Lamin A in maintaining nuclear organization and genome stability, we employed gene silencing (siRNA mediated knockdown) approach to perturb Lamin A levels in a diploid, karyotypically stable, colorectal cancer cell line – DLD1. Our studies show that perturbation of Lamin A causes significant changes in nuclear shape in a manner that does not affect B-type Lamins and only shows small effects on the viability of DLD1 cells. Lamin A knockdown in DLD1 cells shows a subtle modulation in the number of intranuclear Lamin bodies that are required for transcription. Lamin A knockdown significantly shifts the stable diploid phenotype of DLD1 cells and significantly alters copy numbers of two genes - DNMT1 (Chr.19) and WDR8 (Chr.1) irrespective of the chromosomes that they map to. These studies for the first time uncover Lamin A as a modulator of gene copy numbers further reiterating its role in maintaining genome stability. However, knockdown of Lamin A showed differential effects on the 3-dimensional nuclear organization of DNMT1 and WDR8 gene loci with respect to its chromosome territory, suggesting a selective regulatory role of Lamin A in modulating nuclear structure and function.