Telomere Length Dynamics and DNA Damage Responses Associated with Long-Duration Spaceflight

Abstract

Highlights d Astronauts have shorter telomeres than ground controls before and after spaceflight d Inter-individual differences identified in astronaut telomere length after spaceflight d Chronic oxidative stress during spaceflight correlates with telomere length dynamics d Increased frequencies of chromosomal inversions observed during and after spaceflight

Telomere Length Dynamics and Chromosomal Instability for Predicting Individual Radiosensitivity and Risk via Machine Learning

“…When parsing lymphocytes by sub-type and correlating MTL with the proportions of cell-types, positive correlations with NK and CD4 cells (R 2 = 0.408, 0.282), and negative correlations with CD8 and CD19 cells (R 2 = −0.251, −0.288) were observed. These results support our previously proposed supposition that the observed changes in MTL associated with radiation exposure could be at least partially due to cell killing and associated changes in peripheral blood lymphocyte cell populations [78,79].…”

“…Furthermore, longitudinal correlations between MTL and the proportions of lymphocyte sub-groups (all time points, for each patient) revealed positive relationships with natural killer (NK) and CD4 cells (R 2 = 0.408, 0.282), and negative relationships with CD8 and CD19 cells (R 2 = −0.251, −0.288) (Figure S1C). These results support the notion that the overall changes in MTL associated with radiation exposure, specifically apparent telomere elongation, could be at least partially due to cell killing and shifts in lymphocyte populations, as previously proposed [78,79].…”

Telomeric Double Strand Breaks in G1 Human Cells Facilitate Formation of 5′ C-Rich Overhangs and Recruitment of TERRA

“…Such dynamic interactions serve to preserve telomeric 5′ C-rich (ss)overhangs at telomeric DSB sites so that they persist into S/G2 phase ( D’Alessandro et al, 2018 ) for replication (telomerase-mediated) or HR-dependent (ALT) elongation as a means of repair and restoration of functional telomeres. Our results highlight the remarkable adaptability of telomeres, and so have important implications for chronic telomeric DNA damage, such as occurs in extreme environments (e.g., during long-duration spaceflight), in normal human G1/G0 cells with very low levels of telomerase ( Luxton et al, 2020a , b ), as well as for therapeutically relevant targets for disrupting telomere function and improving treatment of ALT-positive tumors.…”

Haplotype diversity and sequence heterogeneity of human telomeres

“…Repeat-rich, low-complexity regions of the human genome such as telomeres have been historically recalcitrant to full mapping and annotation (Miga 2015), mainly owing to the alignment challenge they pose and to the read lengths required to span such areas (Treangen and Salzberg 2012). The advent of long-read, single-molecule methods (third-generation sequencing) has provided new opportunities to map the sequence composition of a previously "dark" area of the human genome, enabling research into the sequence composition and length dynamics (Luxton et al 2020a(Luxton et al , 2020b of telomeres. Our results not only reaffirm that the canonical repeat (5 ′ -TTAGGG-3 ′ ) is certainly the most dominant motif found within telomeres but also reveal a range of diverse, noncanonical repeat variations, which are confirmed by both short-and long-read sequencing technologies.…”