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
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 the S phase checkpoint) when DNA replication is perturbed by various endogenous or exogenous factors. The checkpoint senses the perturbations and stimulates a series of coordinated protective cellular responses such as cell cycle delay, increased production of dNTPs, and protection of perturbed forks from collapsing so that DNA synthesis can resume when perturbations diminish. The long-term goal of our research is to understand how checkpoint signaling is initiated at perturbed forks and how perturbed forks are protected by activated checkpoint. We use the fission yeast S. pombe as the primary model for this study because it is a well-established system for studying the cellular mechanisms that are conserved in humans. In addition, the checkpoint signaling pathways in fission yeast are relatively linear, which promotes unambiguous description of the signaling mechanism. We believe that progress in this study will advance our knowledge about 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 checkpoint signaling in tumor cells.
Based on our recent unexpected genetic data, we are also working on the combination therapies that are based on the clinically used drug hydroxyurea. Hydroxyurea perturbes DNA replication and acitivates the replication checkpoint in all eukaryotic organisms. We hope that the drug combinations can be useful for the treatment of cancer or fungal infections.
My lab is located in room 156 and 158 and the office is in room 160, Biological Sciences Building-II. We are currently recruiting talented graduate students and motivated post-doctoral fellows to join the lab and carry out the exciting research.
- Xu YJ, Khan S, Didier AC, Wozniak M, Liu YF, Singh S, and Nakamura TM (2019) A tel2 mutation that destabilizes the Tel2-Tti1-Tti2 complex eliminates Rad3ATR kinase signaling in the DNA replication checkpoint and leads to telomere shortening in fission yeast. Mol. Cell. Biol. 39(20) e00175-19 https://mcb.asm.org/content/early/2019/07/22/MCB.00175-19
- Singh A, Agarwal A, and Xu YJ (2017) Novel cell-killing mechanisms of hydroxyurea and the implications towards combination therapy for the treatment of fungal infections. Antimicrobiol. Agents Chemother. 61(11) e00374-17. http://aac.asm.org/content/61/11/e00734-17.full
- Singh A and Xu YJ (2017) Heme deficiency sensitizes yeast cells to oxidative stress induced by hydroxyurea. J. Biol. Chem. 292(22) 9088-9103 http://www.jbc.org/content/292/22/9088.full.pdf?sid=da7da422-77f3-4c08-8...
- Xu YJ, Singh A, and Alter GM (2016) Hydroxyurea induces cytokinesis arrest in cells expressing a mutated sterol-14α-demethylase in the ergosterol biosynthesis pathway. Genetics 240, 959-973 http://www.genetics.org/content/204/3/959?etoc
- Singh A and Xu YJ (2016) The cell killing mechanisms of hydroxyurea Genes 7, 99 http://www.mdpi.com/2073-4425/7/11/99.
- Xu YJ (2016) Inner nuclear membrane protein Lem2 facilitates Rad3-mediated checkpoint signaling under replication stress induced by nucleotide depletion in fission yeast. Cell. Signal. 28, 235-245 http://www.sciencedirect.com/science/article/pii/S0898656815300140
- 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 http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0092936
- 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. http://femsyr.oxfordjournals.org/content/12/4/486.long
- 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. http://www.jbc.org/content/286/26/22864.long
- Xu YJ and Leffak, M (2010) ATRIP from TopBP1 to ATR – in vitro activation of a DNA damage checkpoint. Proc. Natl. Acad. Sci. USA. 107:13561-13562 (co-correspondence author). http://www.pnas.org/content/107/31/13561.long
- 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). http://www.jbc.org/content/284/23/16016.long
- 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. http://genesdev.cshlp.org/content/20/8/990.long
- 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. http://www.sciencedirect.com/science/article/pii/S1568786402001945
- 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. http://www.jbc.org/content/273/44/28837.long
- 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. http://link.springer.com/chapter/10.1007%2F978-1-4615-4865-2_6#page-1
- 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. http://pubs.acs.org/doi/abs/10.1021/bi972101o
- 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. http://pubs.acs.org/doi/abs/10.1021/ja963444x Note: C1027 is now renamed as Lidamycin (力达霉素). It is the first structurally new antitumor antibiotic discovered in China.
- 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. ISBN: 9780792340256
- 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. http://pubs.acs.org/doi/abs/10.1021/bi00038a044
- 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. http://pubs.acs.org/doi/abs/10.1021/bi00185a036
- 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) (中国科学 化学) 8:814-819. http://chem.scichina.com:8081/sciB/CN/Y1992/V22/I8/814
- Xu YJ, Li DD, and Zhen YS (1991) Recent advances in the research of macromolecular antitumor antibiotics. Chin. J. Antibiot. (中国抗生素杂志) 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. http://link.springer.com/article/10.1007/BF00689274
Patent Application: The US Patent Application 15/332292 “Combination Therapies for the Treatment of Fungal Infections and Cancer” has been filed on October 24, 2016.
Inventors: Yong-jie Xu and Amanpreet Singh.