For this fiscal year, we have completed the characterization of a histone variant, macroH2A functioning in telomere maintenance in unique human cancers depends on the alternative lengthening of telomeres (ALT), a homology-directed telomere maintenance pathway. ALT telomeres exhibit a unique chromatin environment and generally lack the nucleosome remodeler ATRX, pointing to an epigenetic basis for ALT. Previously, we have identified a protective role for macroH2A1.2 during homologous recombination (HR) and replication stress (RS). Consistent with an inherent susceptibility to RS, we have identified that ALT telomeres are highly enriched for macroH2A1.2. However, in contrast to ATRX-proficient cells, ALT telomeres transiently lose macroH2A1.2 during acute RS to facilitate DSB formation, a process that is almost completely prevented by ectopic ATRX expression. Telomeric macroH2A1.2 is re-deposited in a DNA damage response-dependent manner to promote HR-associated ALT pathways. Our findings thus identify the dynamic exchange of macroH2A1.2 on chromatin as an epigenetic link between ATRX loss, RS-induced DNA damage response initiation and telomere maintenance via HR. This work is recently published in Nat Struct Mol Biol. 2019 Mar;26(3):213-219. A Fanconi anemia protein SLX4 assembles a complex consisting of endonucleases SLX1, MUS81, and XPF and functions in genome maintenance. Our ongoing projects investigate the mechanism and regulation of the SLX4-nuclease complex in genome maintenance. 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-MUS81 interaction and genome integrity, confirming the necessity of these key residues in the functionality of the SLX4 complex in genome 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 |
