Unraveling secrets of telomeres: One molecule at a time

Lin, Jiangguo; Kaur, Parminder; Countryman, Preston; Opresko, Patricia L.; Wang, Hong

doi:10.1016/j.dnarep.2014.01.012

Cited by 23 publications

(21 citation statements)

References 138 publications

(184 reference statements)

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“…Furthermore, depletion of DNA damage–response factors can result in defective telomere maintenance; for example, studies have shown that cells lacking or deficient in certain helicases display telomere attrition and/or replication defects (Crabbe et al 2004; Sfeir et al 2009; Ghosh et al 2011). Human telomeric DNA includes 2–15 kb of tandem repeats of TTAGGG, plus aterminal 3′-protruding G-rich single-stranded DNA (ssDNA) tail greater than 100 nucleotides long (Lin et al 2014). The ssDNA tail folds back and invades the telomeric double-stranded DNA (dsDNA) forming a telomeric T-loop that is critical for telomere capping (Hanish et al 1994).…”

Section: Theories Of Agingmentioning

confidence: 99%

DNA Damage, DNA Repair, Aging, and Neurodegeneration

Maynard

Fang

Scheibye‐Knudsen

et al. 2015

Cold Spring Harb Perspect Med

334

197

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Aging in mammals is accompanied by a progressive atrophy of tissues and organs, and stochastic damage accumulation to the macromolecules DNA, RNA, proteins, and lipids. The sequence of the human genome represents our genetic blueprint, and accumulating evidence suggests that loss of genomic maintenance may causally contribute to aging. Distinct evidence for a role of imperfect DNA repair in aging is that several premature aging syndromes have underlying genetic DNA repair defects. Accumulation of DNA damage may be particularly prevalent in the central nervous system owing to the low DNA repair capacity in postmitotic brain tissue. It is generally believed that the cumulative effects of the deleterious changes that occur in aging, mostly after the reproductive phase, contribute to species-specific rates of aging. In addition to nuclear DNA damage contributions to aging, there is also abundant evidence for a causative link between mitochondrial DNA damage and the major phenotypes associated with aging. Understanding the mechanistic basis for the association of DNA damage and DNA repair with aging and age-related diseases, such as neurodegeneration, would give insight into contravening age-related diseases and promoting a healthy life span.

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Section: Theories Of Agingmentioning

confidence: 99%

DNA Damage, DNA Repair, Aging, and Neurodegeneration

Maynard

Fang

Scheibye‐Knudsen

et al. 2015

Cold Spring Harb Perspect Med

334

197

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“…Telomeres, the tandem nucleotide repeats at chromosome ends, are markers of cellular replicative capacity, senescence, and biological aging [14]. Telomere length (TL) of newly engrafted cells shortens early after HCT as a consequence of the high degree of cellular replication needed to achieve engraftment [15-17].…”

Section: Introductionmentioning

confidence: 99%

Effect of Recipient Age and Stem Cell Source on the Association between Donor Telomere Length and Survival after Allogeneic Unrelated Hematopoietic Cell Transplantation for Severe Aplastic Anemia

Gadalla

Wang

Dagnall

et al. 2016

Biology of Blood and Marrow Transplantation

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We previously showed an association between donor leukocyte relative telomere length (RTL) and post-hematopoietic cell transplantation (HCT) survival in patients with severe aplastic anemia (SAA) who received bone marrow grafts at ages <40 years. Here, we tested the generalizability of the prior findings in an independent validation cohort and by recipient age and stem cell source in the combined discovery and validation cohorts. We used monoplex quantitative real-time PCR to measure RTL in: (1) a new SAA validation cohort of 428 patients (age range, .2 to 77 years) with available pretransplantation donor blood samples in the Center for International Blood and Marrow Transplant Research repository, and (2) 278 patients from the original cohort who had sufficient DNA to repeat RTL testing. We used Cox proportional hazard models to calculate hazard ratios (HRs), and 95% confidence intervals (CIs) across categories of donor RTL. Data from the validation cohort showed no association between donor RTL and patient survival, but further analysis identified differences by recipient age and stem cell source as the likely explanation. In patients <40 years, the HR comparing longest with shortest and middle RTL tertiles = .75; 95% CI, .44 to 1.30 versus HR = 1.05; 95% CI, .59 to 1.89 for patients ≥40 years, P interaction = 37. In bone marrow recipients, the HR = .68; 95% CI, .72 to 1.10 versus HR = 1.29; 95% CI, .64 to 2.62 for peripheral blood stem cell grafts; P interaction = .88. Analyses using data from the 2 cohorts showed a statistically significant survival benefit only in <40-year-old patients receiving bone marrow graft (HR comparing longest and middle RTL tertiles with shortest = .69; 95% CI, .50 to .95, P = .02). The study suggested that the association between donor RTL and post-HCT outcomes in recipients with SAA may vary by recipient age and stem cell source. A larger study is needed to account for multiple comparisons and to further test the generalizability of our findings.

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“…Consequently, telomeres are markers of cellular replicative capacity, cellular senescence, and aging. 1 …”

Section: Introductionmentioning

confidence: 99%