Faculty Opinions recommendation of Mutant nuclear lamin A leads to progressive alterations of epigenetic control in premature aging.

Defective nuclear lamina protein lamin A is associated with premature aging. Casein kinase 2 (CK2) binds the nuclear lamina, and inhibiting CK2 activity induces cellular senescence in cancer cells. Thus, it is feasible that lamin A and CK2 may cooperate in the aging process. Nuclear CK2 localization relies on lamin A and the lamin A carboxyl terminus physically interacts with the CK2α catalytic core and inhibits its kinase activity. Loss of lamin A inLmna-knockout mouse embryonic fibroblasts (MEFs) confers increased CK2 activity. Conversely, prelamin A that accumulates inZmpste24-deficent MEFs exhibits a high CK2α binding affinity and concomitantly reduces CK2 kinase activity. Permidine treatment activates CK2 by releasing the interaction between lamin A and CK2, promoting DNA damage repair and ameliorating progeroid features. These data reveal a previously unidentified function for nuclear lamin A and highlight an essential role for CK2 in regulating senescence and aging.

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Faculty Opinions recommendation of Nuclear lamin A inhibits adipocyte differentiation: implications for Dunnigan-type familial partial lipodystrophy.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1030491.360418 ◽

2006 ◽

Author(s):

Yosef Gruenbaum

Keyword(s):

Adipocyte Differentiation ◽

Lamin A ◽

Partial Lipodystrophy ◽

Nuclear Lamin ◽

Familial Partial Lipodystrophy

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Human WRN is an intrinsic inhibitor of progerin, abnormal splicing product of lamin A

Scientific Reports ◽

10.1038/s41598-021-88325-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

So-mi Kang ◽

Min-Ho Yoon ◽

Su-Jin Lee ◽

Jinsook Ahn ◽

Sang Ah Yi ◽

...

Keyword(s):

Gene Expression ◽

Life Span ◽

Expression Analysis ◽

Gene Expression Analysis ◽

Werner Syndrome ◽

Genetic Disorder ◽

Dna Helicase ◽

Premature Aging ◽

Lamin A ◽

Short Life Span

AbstractWerner syndrome (WRN) is a rare progressive genetic disorder, caused by functional defects in WRN protein and RecQ4L DNA helicase. Acceleration of the aging process is initiated at puberty and the expected life span is approximately the late 50 s. However, a Wrn-deficient mouse model does not show premature aging phenotypes or a short life span, implying that aging processes differ greatly between humans and mice. Gene expression analysis of WRN cells reveals very similar results to gene expression analysis of Hutchinson Gilford progeria syndrome (HGPS) cells, suggesting that these human progeroid syndromes share a common pathological mechanism. Here we show that WRN cells also express progerin, an abnormal variant of the lamin A protein. In addition, we reveal that duplicated sequences of human WRN (hWRN) from exon 9 to exon 10, which differ from the sequence of mouse WRN (mWRN), are a natural inhibitor of progerin. Overexpression of hWRN reduced progerin expression and aging features in HGPS cells. Furthermore, the elimination of progerin by siRNA or a progerin-inhibitor (SLC-D011 also called progerinin) can ameliorate senescence phenotypes in WRN fibroblasts and cardiomyocytes, derived from WRN-iPSCs. These results suggest that progerin, which easily accumulates under WRN-deficient conditions, can lead to premature aging in WRN and that this effect can be prevented by SLC-D011.

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Alterations of nuclear envelope and chromatin organization in mandibuloacral dysplasia, a rare form of laminopathy

Physiological Genomics ◽

10.1152/physiolgenomics.00060.2005 ◽

2005 ◽

Vol 23 (2) ◽

pp. 150-158 ◽

Cited By ~ 80

Author(s):

Ilaria Filesi ◽

Francesca Gullotta ◽

Giovanna Lattanzi ◽

Maria Rosaria D'Apice ◽

Cristina Capanni ◽

...

Keyword(s):

Nuclear Envelope ◽

Protein A ◽

Nuclear Architecture ◽

Mendelian Inheritance ◽

Premature Aging ◽

Lamin A ◽

Lamin B ◽

Lamin B Receptor ◽

Epigenetic Events ◽

Mandibuloacral Dysplasia

Autosomal recessive mandibuloacral dysplasia [mandibuloacral dysplasia type A (MADA); Online Mendelian Inheritance in Man (OMIM) no. 248370 ] is caused by a mutation in LMNA encoding lamin A/C. Here we show that this mutation causes accumulation of the lamin A precursor protein, a marked alteration of the nuclear architecture and, hence, chromatin disorganization. Heterochromatin domains are altered or completely lost in MADA nuclei, consistent with the finding that heterochromatin-associated protein HP1β and histone H3 methylated at lysine 9 and their nuclear envelope partner protein lamin B receptor (LBR) are delocalized and solubilized. Both accumulation of lamin A precursor and chromatin defects become more severe in older patients. These results strongly suggest that altered chromatin remodeling is a key event in the cascade of epigenetic events causing MADA and could be related to the premature-aging phenotype.

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Towards a Drosophila model of Hutchinson–Gilford progeria syndrome

Biochemical Society Transactions ◽

10.1042/bst0361389 ◽

2008 ◽

Vol 36 (6) ◽

pp. 1389-1392 ◽

Cited By ~ 6

Author(s):

Gemma S. Beard ◽

Joanna M. Bridger ◽

Ian R. Kill ◽

David R.P. Tree

Keyword(s):

Drosophila Melanogaster ◽

Premature Aging ◽

Lamin A ◽

Wild Type ◽

Drosophila Model ◽

Numerous Cell ◽

Cellular Abnormalities ◽

Progeria Syndrome ◽

Hutchinson Gilford Progeria Syndrome ◽

Adult Drosophila

The laminopathy Hutchinson–Gilford progeria syndrome (HGPS) is caused by the mutant lamin A protein progerin and leads to premature aging of affected children. Despite numerous cell biological and biochemical insights into the basis for the cellular abnormalities seen in HGPS, the mechanism linking progerin to the organismal phenotype is not fully understood. To begin to address the mechanism behind HGPS using Drosophila melanogaster, we have ectopically expressed progerin and lamin A. We found that ectopic progerin and lamin A phenocopy several effects of laminopathies in developing and adult Drosophila, but that progerin causes a stronger phenotype than wild-type lamin A.

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