Section for Telomere Maintenance
Yie Liu, Ph.D., Senior Investigator
Telomeres are chromosome end capping structures that prevent chromosome termini from being recognized as broken DNA ends. Owing to its G-rich sequence, telomeres are particularly susceptible to oxidative DNA damage, and also to the formation of unusual secondary structures e.g., G-quadruplex, which may severely affect telomere maintenance. Telomere shortening is a hallmark of aging and is associated with age-related pathologies, which underscores the importance of telomere maintenance. Short telomeres are also a principal defining feature of telomere biology disorders, such as dyskeratosis congenita (DC), for which there are no effective pharmaceutical interventions. Emerging evidence suggests a crucial role for DNA damage signaling induced by critically short telomeres, which results in cell growth retardation, cellular senescence, or apoptosis. However, other pathways or cellular defects cannot be ruled out as contributing factors to telomere loss/dysfunction-associated pathophysiology (or telomeropathy). It has been shown that DC patients and late-generation telomerase null mice with critically short telomeres display mitochondrial impairment, which may further increase telomere DNA damage, and thereby accelerate telomeropathy. In addition, telomere loss/dysfunction is associated with chronic low-grade inflammation, which is a contributing factor to various age-related diseases including pulmonary fibrosis, diabetes, and neurodegeneration.
Dr. Liu’s laboratory investigates the hypothesis that oxidative lesions and inadequate DNA structural resolution would impact telomere maintenance and function. Recently, Dr. Liu’s laboratory explored alternative mechanisms for how telomere loss contributes to telomere biology diseases and age-associated organ decline and pathologies. Using a combination of molecular, genetic, and biochemical approaches, Dr. Liu is interested in probing (1) the key genes that modulate oxidative DNA lesions and unique DNA secondary structures at telomeres; (2) the effect of deficient telomere maintenance on human diseases of accelerated aging and cancers; and 3) the molecular pathways whereby impaired mitochondria elicit telomere dysfunction, and its relevance to the telomere loss/dysfunction-mediated pathophysiology (or telomeropathy). These studies will enhance our understanding of how DNA lesions and deficiencies in telomere structure affect telomere maintenance and thus aging and related human diseases.
- Telomere length
- DNA repair
- DNA damage response
- Oxidative stress
- DNA metabolism
- Genome stability
- Mitochondrial dysfunction
- Cell metabolism
- Cellular senescence
- Premature aging
- Telomere Biology Disorder
- Dyskeratosis Congenita
- Fanconi Anemia
Findings and Publications
Sun C, Wang K, Stock J A, Gong Y, Demarest TG, Yang B, Giri N , Harrington L, Alter BP , Savage SA, Bohr VA, Liu Y. Re-equilibration of imbalanced NAD metabolism ameliorates the impact of telomere dysfunction. EMBO J. Nov 2;39(21):e103420. 2020.
Kim J, Sun C, Tran AD, Chin PJ, Ruiz PD, Wang K, Gibbons RJ, Gamble MJ, Liu Y#, Oberdoerffer P(#corresponding authors). The macroH2A1.2 histone variant links ATRX loss to alternative telomere lengthening. Nat Struct Mol Bio. 26:213-219, 2019.
Shi JX, Yang XR, Ballew B, et al. Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma. Nature Genetics, 46:482-6, 2014.
Wan B, Yin J, Horvath K, Sarkar S, Chen Y, Wu J, Wan K, Lu J, Gu P, Yu EY, Lue NF, Chang S, Liu Y,# Lei M.#(#Corresponding authors) SLX4 Assembles a Telomere Maintenance Toolkit by Bridging Multiple Endonucleases with Telomeres. Cell Reports. 4:861-869, 2013.
Lu J. and Liu Y. Deletion of Ogg1 DNA glycosylase results in telomere base damage and length alteration in yeast. EMBO J. 29:398-409. 2010.