The Connection Between Cell Fate and Telomere


ENGİN A. B. , ENGİN A.

PROTEIN KINASE-MEDIATED DECISIONS BETWEEN LIFE AND DEATH, vol.1275, pp.71-100, 2021 (SCI-Expanded) identifier identifier

  • Publication Type: Article / Article
  • Volume: 1275
  • Publication Date: 2021
  • Doi Number: 10.1007/978-3-030-49844-3_3
  • Journal Name: PROTEIN KINASE-MEDIATED DECISIONS BETWEEN LIFE AND DEATH
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, EMBASE, MEDLINE
  • Page Numbers: pp.71-100
  • Keywords: Telomere, Telomerase, Hayflick limit, Shelterin complex, telomeric repeat binding factor 2 (TRF2), DNA damage response (DDR), T-loop, Human telomeric reverse transcriptase (hTERT), DNA double-strand breaks (DSBs), Ataxia-telangiectasia mutated (ATM), Ataxia- and Rad3-related (ATR), Nonhomologous end joining (NHEJ), Homologous recombination (HR), Homology directed repair (HDR), DNA-DAMAGE-RESPONSE, DEPENDENT PROTEIN-KINASE, NF-KAPPA-B, BREAK REPAIR PATHWAY, TRIPLE T COMPLEX, REVERSE-TRANSCRIPTASE, MRE11/RAD50/NBS1 COMPLEX, HOMOLOGOUS RECOMBINATION, DYSFUNCTIONAL TELOMERES, MAMMALIAN TELOMERES
  • Gazi University Affiliated: Yes

Abstract

Abolition of telomerase activity results in telomere shortening, a process that eventually destabilizes the ends of chromosomes, leading to genomic instability and cell growth arrest or death. Telomere shortening leads to the attainment of the "Hayflick limit", and the transition of cells to state of senescence. If senescence is bypassed, cells undergo crisis through loss of checkpoints. This process causes massive cell death concomitant with further telomere shortening and spontaneous telomere fusions. In functional telomere of mammalian cells, DNA contains double--stranded tandem repeats of TTAGGG. The Shelterin complex, which is composed of six different proteins, is required for the regulation of telomere length and stability in cells. Telomere protection by telomeric repeat binding protein 2 (TRF2) is dependent on DNA damage response (DDR) inhibition via formation of T-loop structures. Many protein kinases contribute to the DDR activated cell cycle checkpoint pathways, and prevent DNA replication until damaged DNA is repaired. Thereby, the connection between cell fate and telomere length- associated telomerase activity is regulated by multiple protein kinase activities. Contrarily, inactivation of DNA damage checkpoint protein kinases in senescent cells can restore cell- cycle progression into S phase. Therefore, telomere-initiated senescence is a DNA damage checkpoint response that is activated with a direct contribution from dysfunctional telomeres. In this review, in addition to the above mentioned, the choice of main repair pathways, which comprise non-homologous end joining and homologous recombination in telomere uncapping telomere dysfunctions, are discussed.