Gene expression, chromosome position and lamin A/C mutations

Puckelwartz, Megan J.; Depreux, Frederic; McNally, Elizabeth M.

doi:10.4161/nucl.2.3.16003

Cited by 45 publications

(27 citation statements)

References 46 publications

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“…However, cells from Lmna Ϫ/Ϫ mice do display loss of chromatin integrity with deformation or blebbing of the lamina and nuclear envelope (13). Chromatin changes related to loss of structural shape, in conjunction with transcription regulatory changes (12,14,15), can also alter the DDR, resulting in DNA damage accumulation (16). While chromatin changes have been linked with altered gene expression, altered expression of DDR-related genes due to lamin A/C deficiency have not yet been identified.…”

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confidence: 99%

Lamin A/C Depletion Enhances DNA Damage-Induced Stalled Replication Fork Arrest

Singh

Hunt

Pandita

et al. 2013

Molecular and Cellular Biology

104

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hThe human LMNA gene encodes the essential nuclear envelope proteins lamin A and C (lamin A/C). Mutations in LMNA result in altered nuclear morphology, but how this impacts the mechanisms that maintain genomic stability is unclear. Here, we report that lamin A/C-deficient cells have a normal response to ionizing radiation but are sensitive to agents that cause interstrand cross-links (ICLs) or replication stress. In response to treatment with ICL agents (cisplatin, camptothecin, and mitomycin), lamin A/C-deficient cells displayed normal ␥-H2AX focus formation but a higher frequency of cells with delayed ␥-H2AX removal, decreased recruitment of the FANCD2 repair factor, and a higher frequency of chromosome aberrations. Similarly, following hydroxyurea-induced replication stress, lamin A/C-deficient cells had an increased frequency of cells with delayed disappearance of ␥-H2AX foci and defective repair factor recruitment (Mre11, CtIP, Rad51, RPA, and FANCD2). Replicative stress also resulted in a higher frequency of chromosomal aberrations as well as defective replication restart. Taken together, the data can be interpreted to suggest that lamin A/C has a role in the restart of stalled replication forks, a prerequisite for initiation of DNA damage repair by the homologous recombination pathway, which is intact in lamin A/C-deficient cells. We propose that lamin A/C is required for maintaining genomic stability following replication fork stalling, induced by either ICL damage or replicative stress, in order to facilitate fork regression prior to DNA damage repair.

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confidence: 99%

Lamin A/C Depletion Enhances DNA Damage-Induced Stalled Replication Fork Arrest

Singh

Hunt

Pandita

et al. 2013

Molecular and Cellular Biology

104

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“…Originally, lamin A/C functions were considered as structural, but later nuclear lamina was also shown to participate in cell proliferation and differentiation, mostly through regulation of chromatin organization and transcription [19][20][21][22]. It is proposed that the effect of lamins on the time and hierarchy of gene expression upon proliferation and differentiation is of major importance for the development and tissue specificity of laminopathies.…”

Section: Introductionmentioning

confidence: 98%

Various lamin A/C mutations alter expression profile of mesenchymal stem cells in mutation specific manner

Malashicheva

Bogdanova

Zabirnyk

et al. 2015

Molecular Genetics and Metabolism

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“…The impact of the p.S143P mutation on gene expression Several studies have shown that mutations in lamin A/C cause altered gene expression (Muchir et al, 2007;Puckelwartz et al, 2011). To study whether p.S143P lamin A/C affects general transcription we carried out a whole-genome expression analysis on patient and control cell lines using an Illumina Human HT-12 v.4 expression beadchip.…”

Section: Introductionmentioning

confidence: 99%

Deleterious assembly of the lamin A/C mutant p.S143P causes ER stress in familial dilated cardiomyopathy

West

Gullmets

Virtanen

et al. 2016

Journal of Cell Science

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Mutation of the LMNA gene, encoding nuclear lamin A/C, is a common cause of familial dilated cardiomyopathy (DCM). Among Finnish DCM patients, the founder mutation c.427T>C (p.S143P) is the most frequently reported genetic variant. Here we show that p.S143P lamin A/C is more nucleoplasmic and soluble than wild type lamin A/C and accumulates into large intranuclear aggregates in a fraction of cultured patient fibroblasts as well as in cells ectopically expressing either FLAG- or GFP-tagged p.S143P lamin A. In fluorescence loss in photobleaching (FLIP) experiments, non-aggregated EGFP-tagged p.S143P lamin A is significantly more dynamic. In in vitro association studies p.S143P lamin A failed to form appropriate filament structures but instead assembled into disorganized aggregates similar to those observed in patient cell nuclei. A whole genome expression analysis revealed an elevated unfolded protein response (UPR) in p.S143P lamin A/C expressing cells. Additional endoplasmic reticulum (ER) stress induced by tunicamycin reduced the viability of mutant lamin expressing cells further. In summary, p.S143P lamin A/C affects normal lamina structure and influences the cellular stress response, homeostasis and viability.

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Gene expression, chromosome position and lamin A/C mutations

Cited by 45 publications

References 46 publications

Lamin A/C Depletion Enhances DNA Damage-Induced Stalled Replication Fork Arrest

Lamin A/C Depletion Enhances DNA Damage-Induced Stalled Replication Fork Arrest

Various lamin A/C mutations alter expression profile of mesenchymal stem cells in mutation specific manner

Deleterious assembly of the lamin A/C mutant p.S143P causes ER stress in familial dilated cardiomyopathy

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