In the setting ofZMPSTE24 deficiency, the final step of lamin processing does not occur, resulting in an accumulation of farnesyl-prelamin A. InHutchinson–Gilford progeria syndrome, a 50-amino acid deletion in prelamin A (amino acids 607–656) removes the site for the second endoproteolytic cleavage. Consequently, no mature lamin A is formed, and afarnesylated mutant prelamin A (progerin) accumulates in cells.[9] Thenuclear lamina consist of a two-dimensional matrix of proteins located next to theinner nuclear membrane. Thelamin family of proteins make up the matrix and are highly conserved in evolution. Duringmitosis, the lamina matrix is reversibly disassembled as the lamin proteins arephosphorylated. Lamin proteins are thought to be involved in nuclear stability,chromatin structure and gene expression. Vertebrate lamins consist of two types, A and B. Throughalternate splicing, this gene encodes three type A lamin isoforms.[10]
Early in mitosis,maturation promoting factor (abbreviated MPF, also called mitosis-promoting factor or M-phase-promoting factor) phosphorylates specific serine residues in all three nuclear lamins, causing depolymerization of the lamin intermediate filaments. The phosphorylated lamin B dimers remain associated with the nuclear membrane via theirisoprenyl anchor. Lamin A is targeted to the nuclear membrane by an isoprenyl group but it is cleaved shortly after arriving at the membrane. It stays associated with the membrane through protein-protein interactions of itself and other membrane associated proteins, such asTOR1AIP1 (LAP1). Depolymerization of the nuclear lamins leads to disintegration of the nuclear envelope.Transfection experiments demonstrate that phosphorylation of human lamin A is required for lamin depolymerization, and thus for disassembly of the nuclear envelope, which normally occurs early in mitosis.
Wild type (left) and mutated (right) form of the Ig-fold of lamin A (LMNA, PDB: 1IFR). Normally, arginine 527 (blue) forms asalt bridge with glutamate 537 (magenta), but R527L substitution results in breaking this interaction (leucine is too short to reach glutamate). Models are presented in surface (upper) and in cartoon (lower) representation.[11]
DNA double-strand damages can be repaired by eitherhomologous recombination (HR) ornon-homologous end joining (NHEJ). LMNA promotes genetic stability by maintaining the levels of proteins that have key roles in HR and NHEJ.[18][19] Mouse cells that are deficient for maturation of prelamin A have increased DNA damage and chromosome aberrations, and show increased sensitivity to DNA damaging agents.[20] Inprogeria, the inadequacy of DNA repair, due to defective LMNA, may cause features of premature aging (seeDNA damage theory of aging).
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^Zirn B, Kress W, Grimm T, Berthold LD, Neubauer B, Kuchelmeister K, et al. (April 2008). "Association of homozygous LMNA mutation R471C with new phenotype: mandibuloacral dysplasia, progeria, and rigid spine muscular dystrophy".American Journal of Medical Genetics. Part A.146A (8):1049–1054.doi:10.1002/ajmg.a.32259.PMID18348272.S2CID205309256.
^Liu B, Wang J, Chan KM, Tjia WM, Deng W, Guan X, et al. (July 2005). "Genomic instability in laminopathy-based premature aging".Nature Medicine.11 (7):780–785.doi:10.1038/nm1266.PMID15980864.S2CID11798376.
^Tang K, Finley RL, Nie D, Honn KV (March 2000). "Identification of 12-lipoxygenase interaction with cellular proteins by yeast two-hybrid screening".Biochemistry.39 (12):3185–3191.doi:10.1021/bi992664v.PMID10727209.
^Lattanzi G, Cenni V, Marmiroli S, Capanni C, Mattioli E, Merlini L, et al. (April 2003). "Association of emerin with nuclear and cytoplasmic actin is regulated in differentiating myoblasts".Biochemical and Biophysical Research Communications.303 (3):764–770.doi:10.1016/S0006-291X(03)00415-7.PMID12670476.
^Sakaki M, Koike H, Takahashi N, Sasagawa N, Tomioka S, Arahata K, Ishiura S (February 2001). "Interaction between emerin and nuclear lamins".Journal of Biochemistry.129 (2):321–327.doi:10.1093/oxfordjournals.jbchem.a002860.PMID11173535.
^Clements L, Manilal S, Love DR, Morris GE (January 2000). "Direct interaction between emerin and lamin A".Biochemical and Biophysical Research Communications.267 (3):709–714.doi:10.1006/bbrc.1999.2023.PMID10673356.
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Mounkes LC, Burke B, Stewart CL (October 2001). "The A-type lamins: nuclear structural proteins as a focus for muscular dystrophy and cardiovascular diseases".Trends in Cardiovascular Medicine.11 (7):280–285.doi:10.1016/S1050-1738(01)00126-8.PMID11709282.
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