br Role of dysfunctional telomeres in activation of p

Role of dysfunctional telomeres in activation of p38 MAPK pathway as response to genotoxic stress Telomeres are unique structures at the ends of chromosomes that are located adjacent to more gene rich sub-telomeric regions and comprised of tandem GT-rich repeats, (TTAGGG)n in humans and other vertebrates, with a single-stranded 3′-end overhang and a number of telomere associated proteins [78], [79]. A critical length of the telomere is important in order to prevent its loss which subsequently leads to instable chromosomes and loss of cell viability [15]. Telomere length is maintained by an enzyme called telomerase which is a ribonucleoprotein complex [80]. Telomerase is a reverse transcriptase that synthesizes the 5′ to 3’strand of telomeric DNA by copying a short template sequence using its intrinsic RNA moiety [81], [82]. The expression of telomerase is highly regulated in normal development and ageing but is highly up-regulated in majority of human cancers [83]. Telomeres are associated with a protein complex, formed by six telomere specific proteins namely TRF1 (TERF1), TRF2 (TERF2), TIN2 (TINF2), Rap1 (TERF2IP), TPP1 and POT1 and protects chromosomal ends from degradation and fusion thereby maintaining the genome integrity [84], [85], [86], [87]. This hexaprotein complex is referred as shelterin complex. It acts as protective protein hub for telomeres as it prevents the telomeres from being recognized as a double-strand break, thereby circumventing inappropriate DDR activation and aberrant re-combinational repair [88], [89]. In mammalian order Mitomycin C DSBs are repaired by either homologous recombination (HR) or non-homologous end joining (NHEJ) pathway [90], [91]. Telomeres possesses distinct DNA repair capacity from rest of the genome [92], [93] and have been shown to inhibit NHEJ as a preventive mechanism for end-to-end fusions [94]. NHEJ is a major pathway for repairing of DSBs, which allows the two DNA ends to rejoin and is known to be inhibited in vitro by shelterin components, such as TRF2 and RAP1 [95]. Report suggests that telomeres have the potential to sense genotoxic stress [96]. Deregulation of telomeres can lead to genomic instability and causes genomic defects such as chromosomal rearrangements, telomere fusions and telomere shortening [97], [98]. Telomere shortening causes a DDR which is mediated through ATM [41]. Lack of telomere protection triggers a DDR that involves activation of ATM [84], [99] and activation of ATM is known to activate p38, leading to cell cycle arrest and apoptosis [100]. In stress induced telomere shortening, activation of ATM mediates the activation of p38 thus setting up a synergy between stress induced genome instability and DNA damage response through the crosstalk of p38 with shelterin complex. Thus telomeres play vital role in chronic stress which might be regulated by the protein-protein interaction network of up regulated p38 MAPK, ATM and shelterin complex.
p38 MAPK pathway as drug target The p38 MAPK is a popular target in research-based pharmaceutical industry [101]. It has been evident from numerous studies that p38 MAPK pathway has indispensable role in response to various cellular, environmental stress as well as in inflammation [102]. There are reports implicating p38 signaling plays a critical role in inflammatory diseases, as well as in initiation and progression of tumor. [23], [103]. Activation of p38 MAPK has been reported to be essential for survival of cells in response to stimuli that cause a type of DNA damage. UV, γ-irradiation and chemotherapeutic cancer drugs are considered as genotoxic agents that damage DNA and result in cellular death. These stimuli are strong activators of the p38 MAPK pathway [100]. It has been reported that a combination treatment with UV and 8-methoxypsoralen (8-MOP) in Jurkat T cells activates p38 MAPK pathway [100]. Hence, instead of preventing death, inhibition of p38 MAPK with the pharmacological inhibitor increased death of these cells in a dose dependent manner [104].