Resolution of telomeric DNA structure barriers by specific structure nucleases

National Institute On Aging

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Abstract

Human SLX4 protein assembles a complex consisting of endonucleases SLX1, MUS81, and XPF, which is recruited to telomeres via direct interaction of SLX4 with the telomeric DNA-binding protein TRF2. Our ongoing projects investigate the mechanism and regulation of the SLX4 complex in telomere metabolism. In collaboration with an extramural laboratory, we have determined the crystal structure of SLX4 in complex with its interacting proteins MUS81 and identified key contacts that mediate the interaction. Specific disruption of these key contacts interrupts SLX4-MUS81interaction and telomere maintenance, confirming the necessity of these key residues in the functionality of the SLX4 complex in telomere maintenance. Our data support that the SLX4-nuclease toolkit is a bona fide genome and telomere accessory complex that, in conjunction with other telomere maintenance proteins ensures unhindered, but the regulated progression of telomere maintenance. 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. Recently, in collaboration with an intramural laboratory at NCI, we have identified a histone variant, macroH2A that is highly enriched in telomeres. Our ongoing projects investigate the role of the macroH2A in homologous recombination-dependent telomere maintenance in human cells. In addition to these research activities, we assisted the NIA/IRP laboratory in the characterization of a DNA repair protein, APE1 in telomere maintenance.