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. Some age-related pathologies are associated with abnormal telomere length. 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. Dr. Liu’s laboratory investigates the hypothesis that aberrant resolution of the structural barrier and inadequate oxidative DNA repair at the telomere would impact telomere length homeostasis. Using a combination of molecular, genetic, and biochemical approaches, Liu’s lab probes the involvement of the SLX4-nuclease complex, the RECQ helicases and several key BER proteins in telomere length maintenance. Dr. Liu has identified that oxidative stress and DNA base damage alter telomere length homeostasis and can lead to telomere over-lengthening, while the SLX4-nuclease complex and Bloom’s syndrome helicase (BLM) regulate trimming over-lengthened telomeres by resolving telomeric HJ intermediates. These studies explore the mechanistic basis and regulation of the SLX4-assembled complex and of the BER pathway in maintaining telomere length homeostasis. Ultimately, regulated SLX4-nuclease and BER function may constitute an important component of telomere length regulation in human aging, tumorigenesis, and diseases.
Dr. Liu’s laboratory investigates the role of FA proteins in telomere maintenance. Using in vitro and in vivo approaches, her laboratory has identified molecular mechanisms of SLX4 in telomere maintenance in human cells, in which SLX4 functions as a scaffold to recruit various endonucleases XPF, MUS81, and SLX1 to telomeres via its interaction with TRF2. The SLX4-nuclease-TRF2 complex is required for recombination-based telomere maintenance via resolving telomeric structural barriers. Her laboratory has also probed the regulation of the SLX4-nuclease complex in telomere DNA metabolism and found that the nucleolytic activity of the SLX4-nuclease complex is negatively regulated by the telomere binding proteins and the RecQ helicase protein. Thus, the SLX4-nuclease toolkit is a bona fide telomere accessory complex that, in conjunction with other telomere maintenance proteins, ensures the unhindered, but regulated progression of telomere maintenance. Dr. Liu’s lab has further investigated the molecular and structural basis underlying the function of the SLX4 scaffold in the assembly of the structure-specific endonuclease complex and has demonstrated that SLX4 exists as a dimer, formation of which is driven by hydrophobic contacts located in a protein domain and that disruption of SLX4 dimerization abolishes the SLX4-nuclease complex assembly at telomeres. Her laboratory is currently investigating the role of SLX4 in human cancer survival and human genetic disorders.
Another research area in Dr. Liu’ lab is to explore the role of oxidative DNA base damage in disrupting telomere length homeostasis and the role of base excision repair (BER) in oxidative DNA base repair at telomeres. Oxidative stress may result in a variety of DNA damages. Oxidative DNA base lesions are primarily repaired by BER. The initial step in BER is the removal of the damaged base by a DNA glycosylase. Mammalian and budding yeast cells express several DNA glycosylases with overlapping, yet distinct specificities for different oxidative DNA lesions. Using the mouse and yeast genetic models, Dr. Liu’s laboratory has initiated an investigation into the molecular mechanisms through which oxidative base lesions or DNA glycosylase-deficiencies affect telomere length/function. Her lab has found that several key BER proteins are critical in oxidative base repair and telomere length maintenance. Her long-term goal is to investigate the role of BER deficiency in telomere damage-induced cellular senescence and organismal aging.
- Chromosome Biology
- Genetics and Genomics
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, et al. SLX4 Assembles a Telomere Maintenance Toolkit by Bridging Multiple Endonucleases with Telomeres. Cell Reports. 4(5):861-869, 2013.
Shi JX, et al. Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma. Nature Genetics, 2014. 46(5):482-6.
Sarkar J, et al. SLX4 contributes to telomere preservation and regulated processing of telomeric joint molecule intermediates. Nuc. Acid. Res. 43:5912-23, 2015
Yin J, et al. Dimerization of SLX4 contributes to functioning of the SLX4-nuclease complex. Nuc. Acid. Res. 44:4871-80, 2016