Novel roles for A-type lamins in telomere biology and the DNA damage response pathway

González-Suárez, Ignacio; Redwood, Abena B.; Perkins, Stephanie M.; Vermolen, Bart J.; Lichtensztejin, Daniel; Grotsky, David A; Morgado-Palacin, Lucia; Gapud, Eric J.; Sleckman, Barry P.; Sullivan, Teresa; Sage, Julien; Stewart, Colin L.; Mai, Sabine; Gonzalo, Susana

doi:10.1038/emboj.2009.196

Cited by 213 publications

(273 citation statements)

References 71 publications

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“…Telomere function requires a normal nuclear lamina and dysfunctional, shortened telomeres have been observed in HGPS and lamin A-deficient cells (Taimen et al, 2009;Gonzalez-Suarez et al, 2009;Decker et al, 2009). Our data showed that only lamin mutant cells expressed detectable levels of PIN2/ TRF-1 telomerase inhibitor, whose overexpression leads to shortened telomeres (Zhou et al, 2003).…”

Section: High Throughput Proteomic Analysissupporting

confidence: 51%

Identification of Markers for Cellular Stress and Senescence in Laminopathic Cells by Proteomic Analysis

Sinha¹,

Swamy²,

Muralikrishna³

et al. 2014

Proceedings of the Indian National Science Academy

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Lamins are components of the structural network in the nucleus and play a key role in nuclear organization and function. Mutations in the human lamin A gene cause a spectrum of genetic diseases that include muscular dystrophies, cardiomyopathy, lipodystrophy and premature ageing syndromes. Laminopathic cells display several abnormalities in nuclear morphology and function. We have carried out a comprehensive analysis of alterations in the protein profiles of HEK293T cells expressing a mutation in lamin A (Q294P) that causes Emery-Dreifuss muscular dystrophy, in comparison with cells expressing wild-type lamin A. Initially a total of 27 differentially expressed proteins were identified by quantitative two-dimensional gel electrophoresis followed by mass spectral analysis. Importantly, a 5-fold decrease in lamin B1 levels in mutant cells was observed by quantitative two-dimensional gel electrophoresis, which was supported by immunofluorescence analysis. Changes in levels of specific heat shock proteins, hnRNPs, DNA damage response proteins, metabolic enzymes and cytoskeletal proteins were also observed. Further detailed analysis of cell lysates by one-dimensional gel electrophoresis followed by high throughput mass spectrometry revealed 650 unique proteins from wild-type cells and 1494 unique proteins from mutant cells (with two or more than two peptide hits). Alterations in a number of proteins that are involved in chromatin structure, chromosome condensation, nucleosome assembly, epigenetic modifications, centromere organization, telomere length and DNA repair were observed. These data suggest that laminopathic cells exhibit characteristics of cellular stress and senescence, and provide new insights into the cellular basis of pathologies caused by laminopathic mutations.

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Section: High Throughput Proteomic Analysissupporting

confidence: 51%

Identification of Markers for Cellular Stress and Senescence in Laminopathic Cells by Proteomic Analysis

Sinha¹,

Swamy²,

Muralikrishna³

et al. 2014

Proceedings of the Indian National Science Academy

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“…In addition, we found that loss of A-type lamins leads to decreased levels of 53BP1, due to destabilization of the protein. 45 The decrease in 53BP1 levels is likely to be responsible for the low efficiency of end-to-end fusions upon telomere dysfunction in A-type lamins-deficient H4K20me3. Future experiments need to determine if ALT is the mechanism activated upon loss of Rb family members, and if A-type lamins inhibit recombination at telomeres.…”

Section: Resultsmentioning

confidence: 99%

“…A recent study in our laboratory has shown that A-type lamins bind to mouse telomeres and participate in their nuclear compartmentalization. 45 Embryonic fibroblasts from LMNA null mice exhibit changes in the nuclear distribution of telomeres towards the nuclear periphery and away from the nuclear center. This result was unexpected, since lamins are highly enriched at the nuclear periphery.…”

Section: A-type Lamins and Telomere Structure Length And Functionmentioning

confidence: 99%

“…Thus, A-type lamins, or a process regulated by these proteins, are necessary for the elongation of telomeres upon loss of Rb family members and decrease of are consistently shorter than the corresponding wild-type controls, and exhibit an increase in signal-free ends (loss of telomeric signals). 45 Furthermore, acute depletion of A-type lamins by shRNAs specific for depletion of lamins A and C, leads to telomere shortening after only a few passages of the cells in culture as determined by Quantitative Fluorescence In Situ Hybridization (Q-FISH) with a telomeric probe. Most importantly, reintroduction of either lamin A, lamin C, or both by retroviral transduction of A-type lamins-depleted cells rescues the telomere shortening phenotype to varying degrees (Fig.…”

Section: A-type Lamins and Telomere Structure Length And Functionmentioning

confidence: 99%

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Loss of A-type lamins and genomic instability

González-Suárez¹,

Redwood²,

Gonzalo³

2009

Cell Cycle

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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.

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“…The mechanisms sustaining this particular distribution of mammalian telomeres has never been studied in details and the only data that could be relevant for such a question are the demonstrations of telomeres association to nuclear matrix components, 10,11 transient association with mobile proteins of the Inner Nuclear Membrane (INM) at the end of mitosis 12 and functional relationship between telomere length or homeostasis and lamin A variants. 13 Recent evidence suggests that peripheral positioning and late replication might be concomitant (Arnoult et al, submitted) and that peripheral clustering of telomeres is a hallmark of senescence in human stem cells. 14 involved in enhancer-blocking activity, 7,8 both CTCF and A-type lamins mediate the D4Z4 insulator boundary activity against position effect.…”

Section: Extra Viewmentioning

confidence: 99%