1 INTRODUCTION
Lamins are intermediate filaments commonly called as ‘nuclear proteins’ constituent of a fibrous complex, found primarily in the inner nuclear membrane labeled as nuclear lamina1. Apart from nuclear lamina, it is also present all over in the nucleoplasm2,3. In addition, lamins play an important role in maintaining shape, integrity and function of nucleus during the process of DNA replication and RNA transcription4. Lamin A and lamin C are isomers of lamins, derived from single LMNA gene through alternative splicing process5. Prelamin A contains 664 amino acid residues whereas lamin C has 572 amino acids. After post translational modifications, prelamin A converts into mature lamin A, which has 646 amino acids residues6. Both Lamin A and C, are expressed in all vertebrate cells and considered to be an isoforms of A-type lamins7. A and C type lamins were produced as a dimer throughout the rod domain8,9that are found to be fixed and accumulate on the exterior of mitotic chromosomes at exact places on the rod10,11. Lamin A interacts with a departure of nuclear factors, along with transcriptional regulators, nuclear pore complexes, nuclear membrane-associated proteins and double-stranded DNA, which disrupts lamina and protein progerin that certainly leads to modification of gene expression, and other nuclear defects that leads to genome instability6,12.
Mutations in the lamin A leads to cause 40 different genetic diseases which includes cardio-myopathies, muscular dystrophies and Hutchinson-gilford Progeria Syndrome12,15. Hutchinson-gilford progeria syndrome and Werner syndrome (WS) are the two genetic diseases, well-known for the accelerated aging syndrome (Premature aging) in humans. While maximum instances of WS are due to mutation that occur in WRN helicase16. However, de novo G608G (GGC.GGT) mutation in exon 11 of LMNA cause approximately 90% of the peoples affected with HGPS17,19.
Telomere in vertebrates are composed of TTAGGG repeats bounded by a protein complex “shelterin” known as telosome; this shelterin complex plays very important role in chromosome protection and also in the regulation of telomere length20. However, it helps in maintaining the integrity of chromosome by avoiding unsuitable DNA destruction signaling and restoration at telomere20,21. At the time of dysfunctional in shelterin complex, double-stranded DNA at the chromosomal end breakdown and become subtractive for any one of six DNA-damage-response pathways, eventually it initialize to genome unstableness21,22. Dysfunction of telomere and DNA damage are essential characters of organismal aging and cellular senescence, these are associated with the expansion of multiple chronic inflammatory diseases, together with atherosclerosis, diabetes, and sarcopenia23,24.
In normal cells, telomeres bind with the nuclear membrane and telomere shortening events occurred during the time of metaphase stage; Whereas, faster rate of telomere shortening events happens in lamin A mutated cells that leads to formation of chromosomal fusion. At certain stages of cell cycle, chromosomes show ring like arrangements towards nucleus25. Interaction between telomeres and the nuclear lamina, importantly lamin A/C play the major roles in regulation of telomere length and positioning26. Interaction of lamin A with telomeric complex is not studied well, rather there is lack in understanding the molecular interactions between lamin A protein with trf2 and telomere sequences. Hence, the present study was carried out to find the possible interactive role of wild as well as mutant type lamin A in connection trf2 and telomere.