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

Graziano, Simona; Kreienkamp, Ray; Coll-Bonfill, Núria; Gonzalo, Susana

doi:10.1080/19491034.2018.1454168

Cited by 50 publications

(50 citation statements)

References 153 publications

(157 reference statements)

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“…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.…”

Section: Discussionmentioning

confidence: 85%

“…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 …”

Section: Introductionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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Hutchinson Gilford progeria syndrome (HGPS) is a devastating accelerated aging disease caused by LMNA gene mutation. The truncated lamin A protein produced “progerin” has a dominant toxic effect in cells, causing disruption of nuclear architecture and chromatin structure, genomic instability, gene expression changes, oxidative stress, and premature senescence. It was previously shown that progerin‐induced genomic instability involves replication stress (RS), characterized by replication fork stalling and nuclease‐mediated degradation of stalled forks. RS is accompanied by activation of cGAS/STING cytosolic DNA sensing pathway and STAT1‐regulated interferon (IFN)‐like response. It is also found that calcitriol, the active hormonal form of vitamin D, rescues RS and represses the cGAS/STING/IFN cascade. Here, the mechanisms underlying RS in progerin‐expressing cells and the rescue by calcitriol are explored. It is found that progerin elicits a marked downregulation of RAD51, concomitant with increased levels of phosphorylated‐RPA, a marker of RS. Interestingly, calcitriol prevents RS and activation of the cGAS/STING/IFN response in part through maintenance of RAD51 levels in progerin‐expressing cells. Thus, loss of RAD51 is one of the consequences of progerin expression that can contribute to RS and activation of the IFN response. Stabilization of RAD51 helps explain the beneficial effects of calcitriol in these processes.

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Section: Discussionmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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“…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).…”

Section: High Levels Of Dna Damage Are Associated With R249w Mutationmentioning

confidence: 99%

Consequences of Lmna Exon 4 Mutations in Myoblast Function

Gómez-Domínguez¹,

Epifano²,

Miguel³

et al. 2020

Preprint

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F.M.), bvilaplana@isciii.es (B.V.M.), almmartin@isciii.es (A.M.), rmilla@isciii.es (M.R-M.), iperez@isciii.es (I.P.C.) 2 Fundación Andrés Marcio, niños contra la laminopatía; C/Núñez de Abstract:Laminopathies are causally associated with mutations on Lamin A gene (LMNA). To date, more than 400 mutations in LMNA have been reported in patients. These mutations are widely distributed throughout the entire gene and are associated with a wide range of phenotypes. Unfortunately, little is known about the mechanisms underlying the effect of the majority of these mutations. This is the case of more than 40 mutations that are located at exon 4. Using CRISPR/Cas9 technology, we have generated a collection of Lmna exon 4 mutants in mouse C2C12 myoblasts. These cell models include different types of exon 4 deletions and the presence of R249W mutation, one of the human variants associated with a severe type of laminopathy (LMNA-associated congenital muscular dystrophy). We have characterized these clones by measuring their nuclear circularity, myogenic differentiation capacity in 2D and 3D conditions, DNA damage, and p-ERK and p-AKT levels. Our results indicate that Lmna exon 4 mutants show abnormal nuclear morphology. In addition, levels and/or subcellular localization of different members of the lamin and LINC complex are altered in all these mutants. Whereas no significant differences were observed for ERK and AKT activities, the accumulation of DNA damage was associated to the Lmna p.R249W mutant myoblasts. Finally, significant myogenic differentiation defects were detected in the Lmna exon 4 mutants. These results have key implications in the development of future therapeutic strategies for the treatment of laminopathies.

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“…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).…”

Section: Novel Atypical Mfm-like Subtypesmentioning

confidence: 99%

Myofibrillar myopathy in the genomic context

2018

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Myofibrillar myopathy (MFM) is a group of inherited muscular disorders characterized by myofibril dissolution and abnormal accumulation of degradation products. The diagnosis of muscular disorders based on clinical presentation is difficult due to phenotypic heterogeneity and overlapping symptoms. In addition, precise diagnosis does not always explain the disease etiopathology or the highly variable clinical course even among patients diagnosed with the same type of myopathy. The advent of high-throughput next-generation sequencing (NGS) has provided a successful and cost-effective strategy for identification of novel causative genes in myopathies, including MFM. So far, pathogenic mutations associated with MFM phenotype, including atypical MFM-like cases, have been identified in 17 genes: DES, CRYAB, MYOT, ZASP, FLNC, BAG3, FHL1, TTN, DNAJB6, PLEC, LMNA, ACTA1, HSPB8, KY, PYROXD1, and SQSTM + TIA1 (digenic). Most of these genes are also associated with other forms of muscle diseases. In addition, in many MFM patients, numerous genomic variants in muscle-related genes have been identified. The various myopathies and muscular dystrophies seem to form a single disease continuum; therefore, gene identification in one disease impacts the genetic etiology of the others. In this review, we describe the heterogeneity of the MFM genetic background focusing on the role of rare variants, the importance of whole genome sequencing in the identification of novel disease-associated mutations, and the emerging concept of variant load as the basis of the phenotypic heterogeneity.

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

Cited by 50 publications

References 153 publications

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

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

Consequences of Lmna Exon 4 Mutations in Myoblast Function

Myofibrillar myopathy in the genomic context

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