Xu-Dong Zhu, Ph.D.
Research Interest: Telomere Maintenance and Genome Integrity
Currently accepting highly motivated graduate students.
- Ho, A., Wilson, F.R., Peragine, S.L., Jeyanthan, K., Mitchell, T.R.H. and Zhu, X.-D. (2016) TRF1 phosphorylation on T271 modulates telomerase-dependent telomere lengthen maintenance as well as the formation of ALT-associated PML bodies. Scientific Reports 6: 36913.
- Wilson, F.R., Ho, A., Walker, J.R. and Zhu, X.-D. (2016) Cdk-dependent phosphorylation regulates TRF1 recruitment to PML bodies and promotes C-circle production in ALT cells. J. Cell Sci. 129, 2559-2572
- Tong, A.S., Stern, J.L., Sfeir, A., Kartawinata, M., de Lange, T., Zhu, X.-D. and Bryan, T.M. (2015) ATM and ATR signalling regulate the recruitment of human telomerase to telomeres. Cell Reports 13, 1633-1646.
- Baternburg, N.L., Thompson, E.L., Hendrickson, E.A. and Zhu, X.-D. (2015) Cockayne syndrome group B protein regulates DNA double-strand break repair and checkpoint activation. EMBO J 34, 1399-1416.
- Mitchell, T.R.H. and Zhu, X.-D. (2014) Methylated TRF2 associated with the nuclear matrix and serves as a potential biomarker for cellular senescence. Aging 6, 248-263.
- McKerlie, M., Walker, J.R., Mitchell, T.R.H., Wilson, F.R. and Zhu, X.-D. (2013) Phosphorylated (pT371)TRF1 is recruited to sites of DNA damage to facilitate homologous recombination and checkpoint activation. Nucleic Acids Research 41, 10268-10282.
- Batenburg, N.L., Mitchell, T.R.H., Leach, D.M., Rainbow, A.J. and Zhu, X.-D. (2012) Cockayne syndrome group B protein interacts with TRF2 and regulates telomere length and stability. Nucleic Acids Research 40, 9661-9674.
- Walker, J.R., and Zhu, X.-D. (2012) Post-translational modifications of TRF1 and TRF2 and their roles in telomere maintenance. Ageing Dev. 133, 421-434.
- McKerlie, M., Lin, S. and Zhu, X.-D. (2012) ATM regulates proteasome-dependent subnuclear localization of TRF1, which is important for telomere maintenance. Nucleic Acids Research 40, 3975-3989.
- McKerlie, M. and Zhu, X.-D. (2011) Cyclin B-dependent kinase 1 regulates human TRF1 to modulate the resolution of sister telomeres. Nature Communications 2:371 doi: 10.1038/ncomms1372.
- Mitchell, T.R.H., Glenfield, K., Jeyanthan, K. and Zhu, X.-D. (2009) Arginine methylation regulates telomere length and stability. Cell. Biol. 29, 4918-4934.
- Wu, Y., Mitchell, T. R., and Zhu, X.-D. (2008) Human XPF controls TRF2 and telomere length maintenance through distinctive mechanisms. Ageing Dev. 129, 602-610.
- Wu, Y., Xiao, S., and Zhu, X.-D. (2007) MRE11/RAD50/NBS1 and ATM function as co-mediators of TRF1 in telomere length control. Nature Structural & Molecular Biology 14, 832-840.
- Wu, Y., Zacal N. J., Rainbow, A. J., and Zhu, X.-D. (2007) XPF with mutations in its conserved nuclease domain is defective in DNA repair but functions in TRF2-mediated telomere shortening. DNA Repair 6, 157-166.
- Zhu, X.-D., Niedernhofer, L., Kuster, B., Mann, M., Hoeijmakers, J. H. J., and de Lange, T. (2003) ERCC1/XPF removes the 3’ overhang from uncapped telomeres and represses formation of telomeric DNA-containing double minute chromosomes. Molecular Cell 12, 1489-1498.
- Zhu, X.-D., Kuster, B., Mann, M., Petrini, J. H. J., and de Lange, T. (2000) Cell cycle regulated association of Rad50/Mre11/Nbs1 with TRF2 and human telomeres. Nature Genetics 25, 347-352.
- Zhu, X.-D., and Sadowski, P. D. (1998) The role of single-stranded DNA in Flp-mediated strand exchange. Biol. Chem. 273, 4921-4927.
- Zhu, X.-D., and Sadowski, P. D. (1998) Selection of novel, specific single-stranded DNA sequences by Flp, a duplex-specific DNA binding protein. Nucleic Acids Res. 26, 1329-1336.
- Zhu, X.-D., and Sadowski, P. D. (1995) Cleavage-dependent Ligation by the Flp Recombinase: characterization of a mutant Flp protein with an alteration in a catalytic amino acid. Biol. Chem. 270, 23044-23054.
- Zhu, X.-D., Pan, G., Luetke, K, and Sadowski, P. D. (1995) Homology Requirement for Ligation and Strand Exchange by the Flp Recombinase. Biol. Chem. 270, 11646-11653.
According to Canadian Cancer Society, cancer is the leading cause of premature death in Canada and an estimated one out of every four Canadians is expected to die from cancer. An underlying hallmark of cancer is genome instability, which can arise from the disruption of telomere maintenance. The Zhu laboratory is interested in elucidating the molecular mechanism by which human cells maintain their telomere integrity. Knowledge gained from these studies is expected to aid in the design of anti-cancer therapeutics and treatment of cancer patients.
Currently the Zhu laboratory focuses on two research areas relevant to telomere maintenance and genome integrity:
Elucidating the role of post-translational modifications in telomere maintenance.
Telomeres, heterochromatic structures found at the ends of linear eukaryotic chromosomes, function to protect the natural chromosome ends from being recognized as damaged DNA, thereby helping maintain genomic integrity. Human telomeric DNA is coated with a six-subunit protein complex, referred to as shelterin, which consists of TRF1, TRF2, TIN2, TPP1, POT1 and hRap1. The shelterin complex plays a central role in the maintenance of telomere integrity since loss of shelterin proteins from telomeres can expose chromosome ends for unwanted repair activities, which can lead to genome rearrangement associated with tumorigenesis.
Components of the shelterin complex are subjected to post-translational modifications including phosphorylation, poly(ADP-ribos)ylation, ubiquitylation, SUMOylation, methylation, etc. These modifications play an important role in regulating the cellular localization, stability and function of shelterin proteins. Currently, a major undertaking in the Zhu laboratory is to elucidate the role of phosphorylation in regulating the function of TRF1 and TRF2 as well as to identify the kinases responsible. These studies are expected to reveal additional regulatory pathways important for telomere maintenance.
Elucidating the functional interaction between shelterin proteins and accessary factors.
In addition to shelterin proteins, human telomeres also attract numerous accessory proteins that are not specific to telomeres but play an important role in the maintenance of telomere integrity. These accessory proteins include ATM, Mre11/Rad50/Nbs1, XPF/ERCC1 and CSB.
ATM and the MRN complex are involved in DNA damage response and double-strand break repair and play a central role in maintaining genomic integrity. Mutations in ATM, Mre11 and NBS1 genes give rise to ataxia-telangiectasia (AT), ataxia-telangiectasia-like disease (ATLD) and Nijmegen breakage syndrome (NBS), respectively. Clinically ATLD and NBS are related to AT, which is characterized by immunodeficiency, spontaneous chromosomal instability, hypersensitivity to ionizing radiation and a predisposition to cancer.
XPF/ERCC1 and CSB are involved in nucleotide excision repair responsible for removing UV-induced bulky adducts. Patients with mutations in the XPFgene show repair disorder xeroderma pigmentosum (XP) associated with severe sun sensitivity and high incidence of skin cancer. On the other hand, mutations in the CSB gene give rise to Cockayne syndrome, which is characterized by severe postnatal growth failure, progressive neurological degeneration and segmental premature aging including sensorineural hearing loss, retinal degeneration and loss of subcutaneous fat.
We have shown that these accessary proteins interact with TRF1 and TRF2. Currently we are interested in investigating the mechanisms by which these interactions regulate telomere maintenance and DNA repair.