Resolution of telomeric DNA structure barriers by specific structure nucleases

National Institute On Aging

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Abstract

Fanconi anemia (FA) proteins are functionally grouped into three categories: a core complex, the ID complex, and the downstream effectors. We have previously shown that a downstream effector, SLX4 (also called FANCP) interacts with the telomere repeat binding factor, TRF2 in human cells and recruits several structure-specific endonucleases to telomeres. The SLX4-nuclease complex resolves telomeric joint DNA intermediates via nucleolytic cleavage and regulates telomere length maintenance in human cells. Because uncontrolled nucleolytic cleavage of telomeric DNA would have catastrophic consequences on telomere length maintenance and hence genome stability, we have 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 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., SLX4 contributes to telomere preservation and regulated processing of telomeric joint molecule intermediates. Nucleic Acids Res 43:5912-23). Recently we have investigated the molecular and structural basis underlying the function of the SLX4 scaffold in the assembly of the structure-specific endonuclease complex. We have 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 (Yin J, et al., Dimerization of SLX4 contributes to functioning of the SLX4-nuclease complex. Nuc. Acid. Res. 44:4871-80, 2016). We also contributed to the review articles, describing the recent advance in FA research in the area of telomere biology Sarkar J and Liu Y. Fanconi anemia proteins in telomere maintenance. DNA Repair (Amst). Apr 8. pii: S1568-7864(16)30010-6, 2016; Brosh RM, Bellani M, Liu Y, Seidman MM. Fanconi Anemia: A DNA repair disorder characterized by the accelerated decline of the hematopoietic stem cell compartment and other features of aging. Ageing Research Reviews, May 17. pii: S1568-1637(16)30081-2, 2016.