Yong-jie Xu, PhD
Understanding how 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 DNA replication forks become unstable and may undergo catastrophic collapse, leading to mutagenic chromosomal DNA damage or cell death. For this reason, defects in the DNA replication checkpoint are known causes of genome instability and cancer.
The research interest of my lab is to understand the signaling mechanism of the replication checkpoint (also called intra-S phase checkpoint) when DNA replication is perturbed by various endogenous or exogenous factors. The checkpoint senses the perturbation and stimulates a series of coordinated protective cellular responses such as cell cycle delay, increased production of dNTPs, and stabilization of perturbed replication forks against collapse so that normal DNA synthesis can resume when perturbation diminishes. The long-term goal of our research is to understand how the checkpoint signaling is initiated and how perturbed replication forks are protected by the activated checkpoint during the perturbation. We use the fission yeast Schizosaccharomyces pombe as the primary model organism for this study because it is a well-established system for studying the cellular mechanisms that are conserved in humans. In addition, the replication checkpoint pathway in fission yeast is relatively linear, which promotes unambiguous description of the signaling mechanism. We believe that progress in our study will advance the knowledge of how genome integrity is maintained and how it can be disrupted in human cells. It may also provide therapeutic benefits for cancer chemotherapy designed to interfere with DNA replication or the replication checkpoint in tumor cells.
My lab is located on the first floor in the Diggs Research Laboratory Building. Talented students and motivated post-doctoral fellows are welcome to join our research team.
- Yue M, Zeng L, Singh A, and Xu YJ (2014) Rad4 mainly functions in the Chk1-mediated DNA damage checkpoint pathway as a scaffold protein in Schizosaccharomyces pombe. PLoS ONE 9(3): e92936
- Wang Z, Kim, E, Leffak, M, and Xu YJ (2012) Treslin, DUE-B and GEMC1 cannot complement Sld3 mutants in fission yeast. FEMS Yeast Res. 12, 486-490
- 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.
- Xu YJ and Leffak, M (2010) ATRIP from TopBP1 to ATR – in vitro activation of a DNA damage checkpoint. PNAS. 107:13561-13562 (co-correspondence author).
- Xu YJ and Kelly TJ (2008) Autoinhibition and Activation of the DNA replication checkpoint kinase Cds1. J. Biol. Chem. 284:16016-16027 (co-corresponding author).
- Xu YJ, Davenport M, and Kelly TJ (2006b) Two-stage mechanism for activation of the DNA replication checkpoint kinase Cds1 in fission yeast. Genes & Dev. 20:990-2003
- 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
- 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 ß. J. Biol. Chem. 273:28837-28844.
- Demple B, Bailey E, Bennett RAO, Masuda Y, Wong D, and Xu YJ. 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, 1998.
- 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.
- 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
- 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.
- 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.
- 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.
- 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 (corresponding author).
- Xu YJ, Li DD, and Zhen YS (1991) Recent advances in the research of macromolecular antitumor antibiotics. Chin. J. Antibiot. 6:470-475.
- 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.
M.D.: Peking Union Medical College/Chinese Academy of Medical Sciences
Ph.D.: Biochemistry, Cell and Molecular Biology Program, The Johns Hopkins University School of Medicine
Postdoctoral: Memorial Sloan-Kettering Cancer Center