To date, at least fifteen Fanconi anemia (FA) genes have been identified and their mutations lead to FA, a rare human genetic disease, characterized by progressive bone marrow failure, cancer predisposition, hypersensitive to DNA cross-linking agent, and early mortality. FA proteins are functionally grouped into three categories: a core complex, the ID complex, and the downstream effectors. It has been shown that a downstream effector, SLX4 (also called FANCP) interacts with the telomere repeat binding factor, TRF2 in human cells. We have investigated the role of SLX4 in telomere length regulation and found that SLX4 recruits structure-specific endonucleases, XPF, MUS81, and SLX1 to telomeres via its interaction with TRF2. The SLX4-nuclease-TRF2 complex leads to rapid telomere loss (or telomere trimming) in human cells. Using in vitro and in vivo approaches, my lab has identified molecular mechanisms of SLX4 in telomere trimming, in which SLX4-nuclease-TRF2 complex is involved in the nucleolytic resolution of T-loop and telomere recombination intermediates. Thus, SLX4, together with TRF2, functions as a scaffold to recruit various endonucleases to telomeres for recombination-based telomere maintenance (Wan B. et al., Cell Reports. Sep 12;4:861-869, 2013). Because uncontrolled nucleolytic cleavage of telomeric DNA would have catastrophic consequences on telomere length maintenance and hence genome stability, we have probed the mechanism and regulation of the SLX4 complex in telomere DNA metabolism and found that the nucleolytic activity of the SLX4-nuclease complex is negatively regulated by telomeric proteins TRF1 and TRF2 and by the helicase BLM. Our data support the notion that the SLX4-nuclease toolkit is a bona fide telomere accessory complex that, in conjunction with other telomere maintenance proteins ensures unhindered, but regulated progression of telomere maintenance (Sarkar J. et al., Nuc. Acid. Res. 2015. May 18. pii: gkv52). For the long-term goal, we plan to investigate if SLX4 and its interacting nucleases may initiate telomere loss and contributing to human disease, such as FA. We are also investigating how certain telomeric base lesions alter telomere integrity, thereby contributing to aging and ageing-related diseases. We have examined the impact of dietary and cancer therapeutic intervention induced uracil base substitution of telomeric thymine on telomere length homeostasis and the role of a base excision repair protein, UNG in telomeric uracil base removal. We discovered that accumulation of telomeric uracil and/or UNG deficiency interferes with telomere length, thereby underscoring the necessity of UNG-initiated base excision repair in telomere maintenance (Vallabhaneni V, et al., J. Bio. Chem., 290:5502-11, 2015). Additionally, we assisted in the characterization of RecQ helicase 1 in mammalian telomere maintenance (Popuri V et al., Nuc. Acid. Res. 2014. 42:5671-88) and mutagenesis of a key telomere binding protein POT1 in the biology of human familial cutaneous melanoma. We found that carriers of several POT1 variants had increased telomere lengths, suggesting that these variants perturb POT1 function and thus telomere maintenance (Shi J. et al., Nature Genetics, 2014, 46:482-6).

National Institute of Health (NIH)
National Institute on Aging (NIA)
Investigator-Initiated Intramural Research Projects (ZIA)
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Long, Juanjuan; Huang, Chenhui; Chen, Yanyan et al. (2017) Telomeric TERB1-TRF1 interaction is crucial for male meiosis. Nat Struct Mol Biol 24:1073-1080
Sarkar, Jaya; Liu, Yie (2016) Fanconi anemia proteins in telomere maintenance. DNA Repair (Amst) 43:107-12
Sarkar, Jaya; Wan, Bingbing; Yin, Jinhu et al. (2015) SLX4 contributes to telomere preservation and regulated processing of telomeric joint molecule intermediates. Nucleic Acids Res 43:5912-23
Vallabhaneni, Haritha; Zhou, Fang; Maul, Robert W et al. (2015) Defective repair of uracil causes telomere defects in mouse hematopoietic cells. J Biol Chem 290:5502-11
Popuri, Venkateswarlu; Hsu, Joseph; Khadka, Prabhat et al. (2014) Human RECQL1 participates in telomere maintenance. Nucleic Acids Res 42:5671-88
Shi, Jianxin; Yang, Xiaohong R; Ballew, Bari et al. (2014) Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma. Nat Genet 46:482-6
Vallabhaneni, Haritha; O'Callaghan, Nathan; Sidorova, Julia et al. (2013) Defective repair of oxidative base lesions by the DNA glycosylase Nth1 associates with multiple telomere defects. PLoS Genet 9:e1003639
Lu, Jian; Vallabhaneni, Haritha; Yin, Jinhu et al. (2013) Deletion of the major peroxiredoxin Tsa1 alters telomere length homeostasis. Aging Cell 12:635-44
Ghosh, Avik K; Rossi, Marie L; Singh, Dharmendra Kumar et al. (2012) RECQL4, the protein mutated in Rothmund-Thomson syndrome, functions in telomere maintenance. J Biol Chem 287:196-209
McNeill, Daniel R; Lin, Ping-Chang; Miller, Marshall G et al. (2011) XRCC1 haploinsufficiency in mice has little effect on aging, but adversely modifies exposure-dependent susceptibility. Nucleic Acids Res 39:7992-8004

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