The project includes two parts: 1) Mutations in RecQ-helicase genes associate with autosomal recessive premature aging disorders, often characterized with genome instability and telomere attrition. We are in the process to examine the role of RecQ helicases in telomere length regulation in human cells in collaboration with Dr. Vilhelm Bohr laboratory. In addition, we are screening for helicase-like proteins that associate with telomeres by dual-tag based affinity purification in combination with tandem mass spectrometry approach. We plan to further verify these associations and their roles in telomeres. These studies will unveil potential novel mechanism(s) of how helicases may impact telomere integrity and thus age-related diseases. 2) Telomere shortening has been linked to rare human disorders that present with bone marrow failure including Fanconi anemia. Fancc is one of the most commonly mutated FA genes in FA patients and the Fancc subtype tends to have a relatively early onset of bone marrow failure and hematologic malignancies. We thus studied the role of Fancc in telomere length regulation in mice. Ablation of Fancc exacerbated telomere attrition when murine bone marrow cells experienced high cell turnover. Fancc deficiency led to an increase in telomere-telomere recombination in mice with shortened telomere length. In contrast, this phenotype was not observed in mice with long telomeres. Our data indicate that Fancc deficiency accelerates telomere shortening during high turnover of hematopoietic cells and promotes telomere recombination initiated by short telomeres. Thus, Fancc may suppress cell proliferation-associated telomere attrition and short telomere-initiated telomere recombination, which could, otherwise, promote cell immortalization. Collectively, Fancc may limit hematopoietic cell death or immortalization via regulating telomeres.
| Rhee, David B; Wang, Yisong; Mizesko, Melissa et al. (2010) FANCC suppresses short telomere-initiated telomere sister chromatid exchange. Hum Mol Genet 19:879-87 |
| Giannone, Richard J; Liu, Yie; Wang, Yisong (2009) The monitoring and affinity purification of proteins using dual tags with tetracysteine motifs. Methods Mol Biol 544:421-38 |
