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 and a lariat-like ‘T-loop’ configuration), both of 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 critically short telomere-induced DNA damage signaling, 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 explores 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 telomere maintenance deficiency on human diseases of accelerated aging and cancers; and 3) the molecular pathways that underlie the role of mitochondrial impairment upon 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 structure resolution deficiencies and alternative mechanisms affect telomere maintenance and thus aging and related human diseases.

Portfolio/Research Areas

• Telomere length
• DNA repair
• DNA damage response
• Oxidative stress
• DNA metabolism
• Genome stability
• Mitochondrial dysfunction
• Cell metabolism
• Cellular senescence
• Aging
• Premature aging
• Telomere Biology Disorder
• Dyskeratosis Congenita
• Fanconi Anemia
• Cancer

Findings and Publications

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.

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.

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.

Sarkar J, Wan B, Yin J, Vallabhaneni H, Horvath K, Kulikowicz T, Bohr VA, Zhang Y, Lei M, Liu Y. SLX4 contributes to telomere preservation and regulated processing of telomeric joint molecule intermediates. Nuc. Acid. Res. 43:5912-23, 2015.

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.