DNA Repair and Telomeres — An Intriguing Relationship

Abstract

ment of telomere integrity accompanied by cellular checkpoints abrogation. Quite interestingly, it seems that the pleiotropic effects governing a cell's decision to senesce vs. undergoing apoptosis when reaching the so-called Hayflick limit [9] (certain number of cell divisions), comprise a fertile environment for cancer formation. Cancer cells have developed numerous strategies towards bypassing these limits on the road to achieving eternal proliferation. Genomic stability and telomeresGenomic stability is the prerequisite of species survival as ensures that all required information will be passed on to the next generations. In contrast to single-cell -quickly dividing -species, higher order organisms, in order to preserve their genomic information, require more efficient DNA repair mechanisms due to later onset of reproduction. Therefore, a remarkable ability of cells to recognize and repair DNA damage and progress through the cell cycle, in a regulated and orderly manner, has been developed. A vulnerable portion of the genome, especially in eukaryotic organisms whose genome is organised in linear chromosomes, is their edges called telomeres (after the greek words 'τέλος' (télos) and 'μέρος' (méros) meaning 'the ending part'). Telomeres are nucleoprotein complexes that 'cap' the chromosomes' physical ends. In most eukaryotic organisms integral and stable telomeres guarantee the maintenance of genetic information and its accurate transfer to the next generation. In case telomeres are impaired, abnormal ends are recognised by the DNA damage detection machinery as double-strand DNA (dsDNA) breaks, the DDR is activated and the lesion is healed by Non-Homologous-End-Joining (NHEJ) repair activities. The result of this type of repair may be the fusion of chromosomes and the formation of dicentric /polycentric chromosomes leading in turn to further genomic instability. For this reason a number of telomere-binding protein complexes are associated with telomeres to ensure the formation of a proper secondary structure and a capping function. Intriguingly, a number of protein complexes implicated in DNA repair also contribute to telomere stability. The structure of telomeres is intrinsically dynamic, as chromosome ends should relax during genome replication and then re-establish their 'capped' state after replication. Consequently, telomeres may switch between closed (protected) and open (replication-competent) states during the cell cycle. Each state is governed by a number of interactions with specific factors and can lead the cell to either cell division or senescence / apoptosis under normal conditions, or to disorders / cancer in abnormal cases (processes still poorly understood in a large extent) [10][11]. Moreover, during development and in certain cell types in adults, telomere length should be preserved. Thus, multiple physiological processes guarantee functional and structural heterogeneity of telomeres concerning their length and nucleoprotein composition. A functional chromosome end structure is essential for ...

Genome-nanosurface interaction of titania nanotube arrays: evaluation of telomere, telomerase and NF-κB activities on an epithelial cell model

“…NBN expression is crucial in protecting the telomere integrity from DNA damage-induced checkpoint and the expression of TERF2IP gene may involve in regulating telomere length and protector as the shelterin complex (telosome). 21,22 Noted that the telomere region is more hypersensitive to DNA damage activity under cellular stress condition [22][23][24] which may be resulted from the initial cellular adaptation response on TNA nano-surface.…”

Telomere length analysis in amyotrophic lateral sclerosis using large-scale whole genome sequence data

“…Telomere elongation phenomena are well-documented but far less well-understood than telomere shortening phenomena ( Bryan et al, 1995 ; Cesare and Reddel, 2010 ; Arora and Azzalin, 2015 ; Haycock et al, 2017 ). While telomere shortening is typically seen in cancers, telomere elongation can occur in cancers of the nervous system, and for example, is seen in 25% of primary brain tumors, in glioblastoma multiforme and in 10% of neuroblastomas ( Bryan et al, 1997 ; Hakin-Smith et al, 2003 ; Henson et al, 2005 ; Durant, 2012 ; Boutou et al, 2013 ). In general, cancers in which cells have long telomeres are resistant to therapy and carry a poor prognosis ( Haycock et al, 2017 ).…”