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.
| Li, Mengxia; Yang, Xiao; Lu, Xianfeng et al. (2018) APE1 deficiency promotes cellular senescence and premature aging features. Nucleic Acids Res 46:5664-5677 |
| 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 |
| Yin, Jinhu; Wan, Bingbing; Sarkar, Jaya et al. (2016) Dimerization of SLX4 contributes to functioning of the SLX4-nuclease complex. Nucleic Acids Res 44:4871-80 |
| Sarkar, Jaya; Liu, Yie (2016) The origin of oxidized guanine resolves the puzzle of oxidation-induced telomere-length alterations. Nat Struct Mol Biol 23:1070-1071 |
| 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 |
| Popuri, Venkateswarlu; Hsu, Joseph; Khadka, Prabhat et al. (2014) Human RECQL1 participates in telomere maintenance. Nucleic Acids Res 42:5671-88 |
| Wan, Bingbing; Yin, Jinhu; Horvath, Kent et al. (2013) SLX4 assembles a telomere maintenance toolkit by bridging multiple endonucleases with telomeres. Cell Rep 4:861-9 |
| 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 |
