Mutations in genes coding for Fanconi anemia (FA) proteins lead to FA with early mortality. We and others have found that FA proteins associate with telomeres and their loss impacts telomere length. We hypothesize that FA proteins regulate telomere length by resolving unique telomere DNA structures. To date, at least fifteen FA genes have been identified and 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 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 are currently deciphering potential multiple levels of control to regulate the nucleolytic cleavage activity of the SLX4-nuclease complex, thereby ensuring preservation of telomere maintenance and genome stability. 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.
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