Loss of A-type lamins and genomic instability

Abstract

Research performed in the last few years has revealed important roles for the spatial and temporal organization of the genome on genome function and integrity. A challenge in the field is to determine the molecular mechanisms involved in the organization of genome function. A-type lamins, key structural components of the nucleus, have been implicated in the maintenance of nuclear architecture and chromatin structure. Interestingly, alterations of A-type lamins lead to defects in DNA replication and repair as well as gene transcription and silencing. Elucidating the functions of these proteins is a topical subject since alterations of A-type lamins are associated with a variety of human diseases, ranging from muscular dystrophies and premature aging syndromes to cancer. Here, we discuss novels roles for A-type lamins in the maintenance of telomere structure, length and function as well as in the stabilization of a key DNA damage response factor. These studies support the notion that increased genomic instability due to defects in telomere biology and DNA repair contribute to the pathogenesis of lamin-related diseases.

A dual role for A-type lamins in DNA double-strand break repair

“…Lmna -/-mouse embryonic fibroblasts (MEFs) exhibited increased basal levels of γH2AX, aneuploidy, increased frequency of chromosome and chromatid breaks, and defects in telomere structure, length and function. 15,16 Interestingly, Lmna -/-MEFs were also characterized by defects in NHEJ of dysfunctional telomeres, an example of long-range DSBs processing. The role of A-type lamins in NHEJ of deprotected telomeres and the increased frequency of chromosomal breaks in Lmna -/-MEFs suggest that lamins deficiency might also hinder the ability of cells to repair DNA DSBs that arise during normal metabolic processes-replication fork stalling and generation of reactive oxygen species-or due to exogenous genotoxic insult to the cells.…”

“…In contrast to short-range DNA DSBs repair, the essential role of 53BP1 in long-range NHEJ has been clearly demonstrated. [35][36][37][38] Thus, we hypothesized that the previously reported defects in the processing of dysfunctional telomeres upon loss of A-type lamins 15,16 could be caused by the decrease in 53BP1 levels. To test this hypothesis, U2OS cells were retrovirally transduced with 53BP1 or an empty vector (EV) control followed by lentiviral transduction with a shRNA specific for depletion of A-type lamins (shLmna) or a shRNA control (shCtrl) (Fig.…”

Purkinje Cell Degeneration in pcd Mice Reveals Large Scale Chromatin Reorganization and Gene Silencing Linked to Defective DNA Repair

“…Having established that PC degeneration changes chromatin structure, we then wished to analyze whether this chromatin reorganization occurs at the nuclear periphery, a domain of the genome enriched in repressive marks (2,37). Double immunolabeling for lamin A/C, as a marker of nuclear lamina, and ␥H2AX revealed the typical organization of the nuclear envelope in control PCs in the absence of DNA damage (Fig.…”

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).…”

“…Disruption of the nuclear lamina causes mislocalization of elongation factors, such as proliferating cell nuclear antigen (PCNA) and the replication factor complex (RFC) (Spann et al, 1997). In addition to affecting chromosomal organization and expression, lamin mutations can result in genomic instability by compromising DNA repair through long-range non-homologous endjoining (NHEJ) and homologous recombination (HR), and by affecting telomere structure and function (di Masi et al, 2008;Gonzalez-Suarez et al, 2009a;Gonzalez-Suarez et al, 2009b;Redwood et al, 2011). For example, lamin depletion prevents accumulation of p53-binding protein 1 (53BP1) at double-stranded DNA breaks (Redwood et al, 2011).…”