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.