Resolution of telomeric DNA structure barriers by specific structure nucleases

National Institute On Aging

Investigators

Linked publications, trials & patents

Abstract

We have previously shown that a DNA repair protein, SLX4 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 in human cells. We have recently published the molecular and structural basis underlying the function of the SLX4 scaffold in the assembly of the structure-specific endonuclease complex, by demonstrating 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). Currently, we are investigating the molecular interaction of SLX4 and a structure-specific nuclease, MUS81 in telomere maintenance in eukaryotic organisms. In collaboration with Dr. Ming Lei's laboratory, we have identified the key amino acids that mediate the interaction between SLX4 and MUS81. We found that disrupting SLX4-MUS81 interaction decreases the recruitment of MUS81 to telomeres and the frequency of homologous recombination between telomere sister chromatids in human cells, implying that the SLX4-MUS81 interaction necessitates telomere maintenance in humans (Sun et al. SLX4-MUS81 interaction is required for the function of MUS81 in telomere maintenance. Manuscript in preparation). We also confirmed the similar role of the SLX4 and MUS81 homologs in telomere maintenance in budding yeast, supporting the function of SLX4 and MUS81 is evolutionarily conserved in eukaryotic organisms (Chin PJ, et al. Maintenance of telomeres requires DNA repair and structure resolution proteins in budding yeast. Manuscript in preparation). In addition to these research activities, we contributed the review articles to the peer-viewed journals, describing the recent advance in the areas of telomeric oxidative damage and repair and Fanconi anemia pathway proteins in telomere maintenance Sarkar J, Liu Y. The origin of oxidized guanine resolves the puzzle of oxidation-induced telomere-length alterations. Nat Struct Mol Biol. 23:1070-1071, 2016; Sarkar J, Liu Y (2016) Fanconi anemia proteins in telomere maintenance. DNA Repair (Amst) 43:107-12.