Causes and consequences of genomic instability in laminopathies: Replication stress and interferon response

Abstract

Mammalian nuclei are equipped with a framework of intermediate filaments that function as a karyoskeleton. This nuclear scaffold, formed primarily by lamins (A-type and B-type), maintains the spatial and functional organization of the genome and of sub-nuclear compartments. Over the past decade, a body of evidence has highlighted the significance of these structural nuclear proteins in the maintenance of nuclear architecture and mechanical stability, as well as genome function and integrity. The importance of these structures is now unquestioned given the wide range of degenerative diseases that stem from LMNA gene mutations, including muscular dystrophy disorders, peripheral neuropathies, lipodystrophies, and premature aging syndromes. Here, we review our knowledge about how alterations in nuclear lamins, either by mutation or reduced expression, impact cellular mechanisms that maintain genome integrity. Despite the fact that DNA replication is the major source of DNA damage and genomic instability in dividing cells, how alterations in lamins function impact replication remains minimally explored. We summarize recent studies showing that lamins play a role in DNA replication, and that the DNA damage that accumulates upon lamins dysfunction is elicited in part by deprotection of replication forks. We also discuss the emerging model that DNA damage and replication stress are “sensed” at the cytoplasm by proteins that normally survey this space in search of foreign nucleic acids. In turn, these cytosolic sensors activate innate immune responses, which are materializing as important players in aging and cancer, as well as in the response to cancer immunotherapy.

Calcitriol Prevents RAD51 Loss and cGAS‐STING‐IFN Response Triggered by Progerin

“…Importantly, this study demonstrates a robust effect of calcitriol, hormonal active form of vitamin D, repressing the cGAS/STING/IFN response. Although our previous studies showed this effect in HGPS fibroblasts cultured in the presence of calcitriol for a long period of time (≈90 days) when compared to normal fibroblasts, [2,4,6] now we are able to monitor the activation/repression of these pathways over time. In fact, we find that pre-treatment of cells with calcitriol prevents RAD51 loss, replication stress, and activation of cGAS/STING/IFN pathway upon progerin expression.…”

“…In addition, changes in the expression of lamins, especially downregulation, have been associated with poor prognosis in many cancers . These data and the role of lamins in the maintenance of genome stability and function provide evidence for lamins functioning as “genome caretakers.” Although many studies support that lamins are important for DNA repair, DNA replication, and telomere biology, the underlying mechanisms remain poorly understood …”

“…Although many studies support that lamins are important for DNA repair, DNA DOI: 10.1002/pmic.201800406 replication, and telomere biology, the underlying mechanisms remain poorly understood. [4,5] Our previous studies in progerinexpressing cells revealed accumulation of DNA damage and replication stress (RS). [6,7] In fact, the replication defects in progerin-expressing cells are more robust than in lamin-depleted cells, causing replication fork (RF) stalling in addition to fork degradation by nucleases.…”

Consequences of Lmna Exon 4 Mutations in Myoblast Function

“…We also wanted to study the effect of Lmna-exon-4 mutations at the DNA level, since progeroid and striated muscle laminopathies have been associated with high levels of DNA damage [23][24][25][26]. Quantification of DNA damage by staining for H2AX revealed elevated levels of DNA damage in the R249W clone while no signal was detected in the rest of mutants (Null and Delta) or Controls (Figure 8a).…”

Myofibrillar myopathy in the genomic context

“…Lamin A and lamin B play a role in DNA replication and influence various cellular mechanisms that maintain genome integrity and consequently innate immune response. Therefore, defects in lamin functioning could indirectly contribute to muscle disorders (Graziano et al 2018).…”