Department of Biochemistry & Molecular Biology

Michael Leffak, Ph.D., Interim Chair

Dr. Xu

 

Yong-jie Xu, M.D., Ph.D.

Assistant Professor
Office: 148 Diggs Lab
Lab: 135 Diggs Lab
Phone: (937) 775-4693
E-mail: yong-jie.xu@wright.edu

Education:

M.D.: Peking Union Medical College/Chinese Academy of Medical Sciences (Dian-dong Li & Yong-su Zhen)
Ph.D.: Biochemistry, Cell and Molecular Biology Program, Johns Hopkins University School of Medicine (Thomas J. Kelly)
Postdoctoral: Harvard Medical School (Irving H. Goldberg), Harvard School of Public Health (Bruce Demple) and Memorial Sloan-Kettering Cancer Center (Thomas J. Kelly)

Research Interests

Understanding how eukaryotic genome integrity is maintained over generations – during which time the genome has to be accurately duplicated in each cell cycle – is one of the fundamental problems of modern biology. It is also a critical aspect of the more general problem of understanding the mechanisms that control cellular proliferation and prevent oncogenesis. The stability of the genome depends upon the precise operation of the DNA replication machinery and upon the checkpoint mechanism that deals with various perturbations of DNA replication. If undetected by the checkpoint, perturbed replication forks become unstable and may undergo catastrophic collapse, resulting in cell death or mutagenic chromosomal damage. For this reason, defects in the DNA replication checkpoint are known causes of genome instability and cancer.

My laboratory is interested in understanding the molecular mechanism of the replication checkpoint, a complex signaling pathway that is activated when DNA replication is perturbed. The checkpoint senses the perturbed DNA replication forks and elicits protective cellular responses such as cell cycle delay, stimulated production of deoxyribonucleotides, and more importantly, stabilization of perturbed forks against collapse so that normal DNA synthesis can resume when perturbations are eliminated. The long-term goal of the research program is to better understand the molecular interface between the DNA replication machinery and the checkpoint pathway in order to provide insights into how the checkpoint signaling is initiated at the perturbed replication forks and how perturbed forks are stabilized under stress, the two most prominent questions in the field. We use the fission yeast Schizosaccharomyces pombe as the primary working model organism because the signaling pathway of the replication checkpoint in fission yeast is relatively linear, which may provide an unambiguous description of the signaling mechanism. Progress in the study of the checkpoint signaling mechanism in fission yeast will ultimately advance our knowledge of how genome integrity is maintained and how it can be disrupted in all eukaryotic cells. It may also have implications to an improvement of chemotherapy designed to interfere with the DNA replication or the replication checkpoint in tumor cells.

We are located in the Diggs Research Laboratory Building. Talented graduate students and motivated post-doctoral fellows are welcome to join our research team.

Selected Publications

  1. Yue M, Singh A, Wang Z and Xu YJ (2011) The phosphorylation network for efficient activation of the DNA replication checkpoint in fission yeast. J. Biol. Chem. 286:22864-22874.
  2. Xu YJ and Leffak M (2010) ATRIP from TopBP1 to ATR - in vitro activation of a DNA damage checkpoint. Proc. Natl. Aced. Sci. USA 107:13561-13562.
  3. Xu YJ and Kelly TJ (2009) Autoinhibition and autoactivation of the DNA replication checkpoint kinase Cds1. J. Biol. Chem. 284:16016-16027.
  4. Xu YJ, Davenport M, Kelly TJ (2006) Two-stage mechanism for activation of the DNA replication checkpoint kinase Cds1 in fission yeast. Genes & Dev. 20:990-2003.
  5. Xu YJ, DeMott MS, Hwang JJ, Greenberg MM, and Demple, B. (2003) Action of human apurinic endonuclease (Ape1) on C1-oxidized deoxyribose damage in DNA. DNA Repair 2:175-185.
  6. Xu YJ, Kim E, and Demple B (1998) Excision of C4-oxidized deoxyribose lesions from double-stranded DNA by human apurinic endonuclease (Ape1 protein) and DNA polymerase β. J. Biol. Chem. 273:28837-28844.
  7. Demple B, Bailey E, Bennett RAO, Masuda Y, Wong D, and Xu YJ (1998) Roles of AP endonucleases in repair and genetic stability, in DNA Damage and Repair: Oxygen Radical Effects, Cellular Protection, and Biological Consequences. Ed. M. Dizdaroglu, Plenum Press, New York.
  8. Xu YJ, Xi Z, Zhen YS, and Goldberg IH (1997a) Mechanism of formation of novel covalent drug.DNA interstrand cross-links and monoadducts by enediyne antitumor antibiotics. Biochemistry 36:14975-14984.
  9. Xu YJ, Zhen YS, and Goldberg IH (1997b) Enediyne C1027 induces the formation of novel covalent DNA interstrand cross-links and monoadducts. J. Am. Chem. Soc. 119:1133-1134.
  10. Goldberg IH, Kappen LS, Xu YJ, Stassinopoulos A, Zeng XP, Xi Z, and Yang CF (1995) Enediynes as probes of nucleic acid structure, in NATO Workshop on DNA cleavers and chemotherapy of cancer or viral diseases. Ed. B. Meunnier, Kluwer, Dordrecht, The Netherlands.
  11. Xu YJ, Zhen YS, and Goldberg IH (1995) A single binding mode of activated enediyne C1027 generates two types of double-strand DNA lesions: deuterium isotope-induced shuttling between adjacent nucleotide target sites. Biochemistry 34:12451-12460.
  12. Xu YJ, Zhen YS, and Goldberg IH (1994) C1027 chromophore, a new enediyne antitumor antibiotic, induces sequence-specific double-strand DNA cleavage. Biochemistry 33:5947-5953.
  13. Xu YJ, Li DD, and Zhen YS (1992) Molecular mechanism of C1027, a new antitumor antibiotic with highly potent cytotoxicity (Formation of abasic sites, single- and double-strand breaks in DNA and selective cleavage in the linker regions of nucleosomes). Science in China (Series B) 8:814-819.
  14. Xu YJ, Li DD, and Zhen YS (1991) Recent advances in the research of macromolecular antitumor antibiotics. Chin. J. Antibiot. 6:470-475.
  15. Xu YJ, Li DD, and Zhen YS (1990) Mode of action of C1027, a new macromolecular antitumor antibiotic with highly potent cytotoxicity, on human hepatoma BEL-7402 cells.Cancer Chemother. Pharmacol. 27:41-46.