Telomeres and Telomerase in the Radiation Response: Implications for Instability, Reprograming, and Carcinogenesis

Abstract

Telomeres are nucleoprotein complexes comprised of tandem arrays of repetitive DNA sequence that serve to protect chromosomal termini from inappropriate degradation, as well as to prevent these natural DNA ends from being recognized as broken DNA (double-strand breaks) and triggering of inappropriate DNA damage responses. Preservation of telomere length requires telomerase, the specialized reverse transcriptase capable of maintaining telomere length via template-mediated addition of telomeric repeats onto the ends of newly synthesized chromosomes. Loss of either end-capping function or telomere length maintenance has been associated with genomic instability or senescence in a variety of settings; therefore, telomeres and telomerase have well-established connections to cancer and aging. It has long been recognized that oxidative stress promotes shortening of telomeres, and that telomerase activity is a radiation-inducible function. However, the effects of ionizing radiation (IR) exposure on telomeres per se are much less well understood and appreciated. To gain a deeper understanding of the roles, telomeres and telomerase play in the response of human cells to IRs of different qualities, we tracked changes in telomeric end-capping function, telomere length, and telomerase activity in panels of mammary epithelial and hematopoietic cell lines exposed to low linear energy transfer (LET) gamma(γ)-rays or high LET, high charge, high energy (HZE) particles, delivered either acutely or at low dose rates. In addition to demonstrating that dysfunctional telomeres contribute to IR-induced mutation frequencies and genome instability, we reveal non-canonical roles for telomerase, in that telomerase activity was required for IR-induced enrichment of mammary epithelial putative stem/progenitor cell populations, a finding also suggestive of cellular reprograming. Taken together, the results reported here establish the critical importance of telomeres and telomerase in the radiation response and, as such, have compelling implications not only for accelerated tumor repopulation following radiation therapy but also for carcinogenic potential following low dose exposures as well, including those of relevance to spaceflight-associated galactic cosmic radiations.

Estimation of Radiation Doses to U.S. Military Test Participants from Nuclear Testing: A Comparison of Historical Film-Badge Measurements, Dose Reconstruction and Retrospective Biodosimetry

“…Here, we hypothesized a priori that inclusion of inversions could improve retrospective biodosimetry for estimating exposures that took place over six decades in the past, reasoning that their persistence and higher induction rate per unit dose would be favorable for retrospective dose estimation. Furthermore, we hypothesized that changes in telomere length [e.g., shortening, see (35)] might also reflect these past radiation exposures, thereby providing insight into potential long-term biological and overall health implications [see (12)]. These considerations were the basis for the design of an assessment based on both inversions and translocations.…”

Hole Migration in Telomere‐Based Oligonucleotide Anions and G‐Quadruplexes

“…Telomerase inhibition is thus widely considered as an attractive strategy in cancer therapy . Telomerase dysfunction and telomere length also strongly influence the response of organisms, cells and genomes to the action of ionizing radiation . In living cells, dTTAGGG repetitions in the single‐stranded 3′ overhang can fold into stable four‐stranded G‐quadruplex structures with a high propensity.…”

Evaluating biomarkers to model cancer risk post cosmic ray exposure

“…A number of studies have reported an increase in telomerase activity with radiation exposure ( Hande et al, 1998 ; Leteurtre et al, 1997 ). This induction appears to be cell type specific ( Finnon et al, 2000 ; Sishc et al, 2015 ) and exhibits dose-dependence and temporal kinetics. Increase in activity has been noted as early as 0.5 h and up to 24 h following exposure of fibroblasts and lymphoblasts to low-LET radiation.…”

“…Recent studies have shown that reactivation of telomerase can trigger cellular reprogramming and enrichment of putative stem cell populations post radiation exposure ( Sishc et al, 2015 ). The contribution of the mean telomere length, the length of the shortest telomere, and the degree of telomerase activation that drives these cell fate decisions is unclear.…”

“…Thus far, current studies have primarily been carried out using mono energetic beams of single HZE ions e.g. low- (1 keV/µm) and high-LET protons (28.5 keV/µm), carbon ions (50 keV/µm) ( Berardinelli et al, 2010 , 2015 ), or Fe ions (1 GeV/n) ( Sishc et al, 2015 ) at doses ranging from 1–8 Gy, in comparison to X-rays. The temporal decision to lengthen or shorten telomeres or reactivate telomerase depends on various factors.…”