Key Words: DNA damage and repair, genomic instability, gene targeting, DNA structure, cancer therapeutics
Our research efforts are focused in three general areas within an overall theme of genome instability, DNA damage and mechanisms of repair. A unique feature of our approach is an emphasis on the role of DNA structure, including non-canonical structures such as triplex DNA, as recognition sites for repair machinery, sources of genomic instability, and as a basis for technology to target DNA damage to specific genomic sites.
1. DNA structure in genomic instability and human disease.
The consequences of genomic instability are causative factors for several human diseases that involve repetitive DNA sequences. Many repetitive sequences are able to adopt non-B secondary structures. Interestingly, many of these repeats occur near breakpoints of chromosomal translocations, implicating them in cancer etiology. One example is the H-DNA-forming sequence in the human c-MYC gene that maps to breakage hotspots in Burkitt's lymphoma, that we have discovered is both mutagenic and induces DNA double-strand breaks in mammalian cells. These exciting results provide the first evidence that naturally occurring H-DNA structures are mutagenic; they also support a role for DNA structure in oncogenic translocations. Our studies will determine the mutagenic potential and mechanistic role of non-canonical DNA structures in human disease, with an emphasis on translocation-mediated cancers.
2. Molecular mechanisms of DNA damage recognition and repair.
Defects in DNA repair systems can lead to severe clinical disorders; for example, it is estimated that ~90% of human cancers result from improperly repaired DNA damage. Our work aims to elucidate the molecular basis of damage recognition in order to develop a better understanding of the mutagenic potential and cancer risks of different types of DNA lesions.
3. Novel strategies to modify gene structure and function in living organisms.
An area of intense investigation in my laboratory is the development of triplex technology to improve the existing gene targeting methods by directing damage to specific genomic sites to increase the frequency of recombination and to direct gene inactivation. Our objective is to improve the utility of triplex technology as a tool for genetic manipulation in animals and to develop novel therapeutic strategies for treating cancer.
Education & Training
Current Academic Appointments
Professor, Fellow of the Coulter R. Sublett Chair, College of Pharmacy, Division of Pharmacology and Toxicology, University of Texas at Austin, Austin, TX
Adjunct Professor, Department of Carcinogenesis, Science Park, Research Division, The University of Texas M.D. Anderson Cancer Center, Smithville, TX
Adjunct Professor, Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, TX
1996 Baylor College of Medicine, Houston, TX, Doctor of Philosophy, Biochemistry
1987 University of Miami, Coral Gables, FL, BS, Biology, Marine Science
1997-2000 Postdoctoral Fellowship, Yale University School of Medicine, Department of Therapeutic Radiology, New Haven, CT
1996-1997 Postdoctoral Associate, Baylor College of Medicine, Deparment of Biochemistry, Houston, TX
Peer-Reviewed Original Research Articles
1. Boulware SB, Christensen LA, Thames H, Coghlan L, Vasquez KM, Finch RA.Triplex-forming oligonucleotides targeting c-MYC potentiate the anti-tumor activity of gemcitabine in a mouse model of human cancer. Mol Carcinog. 2013 May 16. doi: 10.1002/mc.22026.
2. Wang Y, Leung JW, Jiang Y, Lowery MG, Do H, Vasquez KM, Chen J, Wang W, Li L. FANCM and FAAP24 maintain genome stability via cooperative as well as unique functions. Mol Cell. 2013 Mar 7;49(5):997-1009. doi: 10.1016/j.molcel.2012.12.010. Epub 2013 Jan 17.
3. Wojcik EA, Brzostek A, Bacolla A, Mackiewicz P, Vasquez KM, Korycka-Machala M, Jaworski A, Dziadek J.Direct and inverted repeats elicit genetic instability by both exploiting and eluding DNA double-strand break repair systems in mycobacteria. PLoS One. 2012;7(12):e51064. doi: 10.1371/journal.pone.0051064. Epub 2012 Dec 10.
4. Abel EL, Boulware S, Fields T, McIvor E, Powell KL, DiGiovanni J, Vasquez KM, MacLeod MC. Sulforaphane induces phase II detoxication enzymes in mouse skin and prevents mutagenesis induced by a mustard gas analog. Toxicol Appl Pharmacol. 2013 Feb 1;266(3):439-42. doi: 10.1016/j.taap.2012.11.020. Epub 2012 Nov 30.
5. Boulware S, Fields T, McIvor E, Powell KL, Abel EL, Vasquez KM, MacLeod MC.2,6-Dithiopurine, a nucleophilic scavenger, protects against mutagenesis in mouse skin treated in vivo with 2-(chloroethyl) ethyl sulfide, a mustard gas analog. Toxicol Appl Pharmacol. 2012 Sep 1;263(2):203-9. doi: 10.1016/j.taap.2012.06.010. Epub 2012 Jun 23.
6. Bacolla A, Wang G, Jain A, Chuzhanova NA, Cer RZ, Collins JR, Cooper DN, Bohr VA, Vasquez KM.Non-B DNA-forming sequences and WRN deficiency independently increase the frequency of base substitution in human cells. J Biol Chem. 2011 Mar 25;286(12):10017-26. Epub 2011 Feb 1.
7. Jain A, Bacolla A, Chakraborty P, Grosse F, Vasquez KM. Human DHX9 helicase unwinds triple-helical DNA structures. Biochemistry. 2010 Aug 24;49(33):6992-9.
8. Kha DT, Wang G, Natrajan N, Harrison L, Vasquez KM. Pathways for double-strand break repair in genetically unstable Z-DNA-forming sequences. J Mol Biol. 2010 May 14;398(4):471-80. Epub 2010 Mar 27. PMID: 20347845
9. Powell KL, Boulware S, Thames H, Vasquez KM, MacLeod MC. 2,6-Dithiopurine blocks toxicity and mutagenesis in human skin cells exposed to sulfur mustard analogues, 2-chloroethyl ethyl sulfide and 2-chloroethyl methyl sulfide. Chem Res Toxicol. 2010 Mar 15;23(3):497-503.PMID: 20196133
10. Zhao J, Bacolla A, Wang G, Vasquez KM. Non-B DNA structure-induced genetic instability and evolution. Cell Mol Life Sci, 9/1/2009. e-Pub 9/1/2009. PMID: 19727556.
11. Liu Y, Nairn RS, Vasquez KM. Targeted gene conversion induced by triplex-directed psoralen interstrand crosslinks in mammalian cells. Nucleic Acids Res, 9/2/2009. e-Pub 9/2/2009. PMID: 19726585.
12. Lange SS, Reddy MC, Vasquez KM. Human HMGB1 directly facilitates interactions between nucleotide excision repair proteins on triplex-directed psoralen interstrand crosslinks. DNA Repair (Amst) 8(7):865-72, 7/2009. e-Pub 5/14/2009. PMCID: PMC2700216.
13. Kolb J, Chuzhanova NA, Hogel J, Vasquez KM, Cooper DN, Bacolla A, Kehrer-Sawatzki H. Cruciform-forming inverted repeats appear to have mediated many of the microinversions that distinguish the human and chimpanzee genomes. Chromosome Res. e-Pub 5/28/2009. PMID: 19475482.
14. Zhao J, Jain A, Iyer RR, Modrich PL, Vasquez KM. Mismatch repair and nucleotide excision repair proteins cooperate in the recognition of DNA interstrand crosslinks. Nucleic Acids Res. e-Pub 5/25/2009. PMID: 19468048.
15. Betous R, Rey L, Wang G, Piliare MJ, Puget N, Selves J, Biard DS, Shin-ya K, Vasquez KM, Cazaux C, Hoffman JS. Role of TLS DNA polymerases eta and kappa in processing naturally occurring structured DNA in human cells. Mol Carcinog 48(4):369-78, 4/2009. PMCID: PMC2696892.
16. Wang G, Carbajal S, Vijg J, DiGiovanni J, Vasquez KM. DNA structure-induced genomic instability in vivo. J Natl Cancer Inst 100(24):1815-7, 12/2008. e-Pub 12/9/2008. PMCID: PMC2639325.
17. Christensen LA, Wang H, Van Houten B, Vasquez KM. Efficient processing of TFO-directed psoralen DNA interstrand crosslinks by the UvrABC nuclease. Nucleic Acids Res 36(22):7136-45, 12/2008. e-Pub 11/7/2008. PMCID: PMC2602775.
18. Wu Q, Vasquez KM. Human MLH1 protein participates in genomic damage checkpoint signaling in response to DNA interstrand crosslinks, while MSH2 functions in DNA repair. PLoS Genet 4(9):e1000189, 9/2008. PMCID: PMC2526179.
19. Liu Y, Nairn RS, Vasquez KM. Processing of triplex-directed psoralen DNA interstrand crosslinks by recombination mechanisms. Nucleic Acids Res 36(14):4680-8, 8/2008. PMCID: PMC2504320.
20. Lange SS, Mitchell DL, Vasquez KM. High mobility group protein B1 enhances DNA repair and chromatin modification after DNA damage. Proc Natl Acad Sci U S A 105(30):10320-5, 7/2008. PMCID: PMC2492475.
21. Ditlevson JV, Tornaletti S, Belotserkovskii BP, Teijeiro V, Wang G, Vasquez KM, Hanawalt PC. Inhibitory effect of a short Z-DNA forming sequence on transcription elongation by T7 RNA polymerase. Nucleic Acids Res 36(10):3163-70, 6/2008. PMCID: PMC2425487.
22. Benfield AP, Macleod MC, Liu Y, Wu Q, Wensel TG, Vasquez KM. Targeted generation of DNA strand breaks using pyrene-conjugated triplex-forming oligonucleotides. Biochemistry 47(23):6279-88, 6/2008. PMCID: PMC2662494.
23. Belotserkovskii BP, di Silva E, Tornaletti S, Wang G, Vasquez KM, Hanawalt PC. A triplex-forming sequence from the human c-Myc promoter interferes with DNA transcription. J Biol Chem 282(44):32433-41, 11/2007. PMID: 17785457.
24. Wu Q, Kiguchi K, Kawamoto T, Ajiki T, Traag J, Carbajal S, Ruffino L, Thames H, Wistuba I, Thomas M, Vasquez KM, DiGiovanni J. Therapeutic effect of rapamycin on gallbladder cancer in a transgenic mouse model. Cancer Res 67(8):3694-800, 4/2007. PMID: 17440093.
25. Wu Q, Gaddis SS, MacLeod MC, Walborg EF, Thames HD, DiGiovanni J, Vasquez KM. High affinity triplex-forming oligonucleotide target sequences in mammalian genomes. Mol Carcinog 46(1):15-23, 1/2007. PMID: 17013831.
26. Christensen LA, Finch RA, Booker AJ, Vasquez KM. Targeting oncogenes to improve breast cancer chemotherapy. Cancer Res 66(8):4089-94, 4/2006. PMID: 16618728.
27. Wang G, Christensen LA, Vasquez KM. Z-DNA-forming sequences generate large-scale deletions in mammalian cells. Proc Natl Acad Sci U S A 103(8):2677-82, 2/2006. PMCID: PMC1413824.
28. Gaddis SS, Wu Q, Thames HD, DiGiovanni J, Wahlborg EF, MacLeod MC, Vasquez KM. A web-based search engine for triplex-forming oligonucleotide target sequences. Oligonucleotides 16(2):196-201, 2006. PMID: 16764543.
29. Lu X, Zhang N, Vasquez K, Barton M, Legerski R. Repair of psoralen interstrand cross-links in Xenopus laevis egg extracts is highly mutagenic. Biochem Biophys Res Commun 336(1):69-75, 10/2005. PMID: 16125670.
30. Wu Q, Christensen LA, Legerski RJ, Vasquez KM. Mismatch repair participates in error-free processing of DNA interstrand crosslinks in human cells. EMBO Rep 6(8):551-7, 6/2005. PMCID: PMC1369090.
31. Reddy MC, Christensen J, Vasquez KM. Interplay between human high mobility group protein 1 and replication protein A on psoralen-cross-linked DNA. Biochemistry 44(11):4188-95, 3/2005. PMID: 15766246.
32. Thoma BS, Wakasugi M, Christensen J, Reddy MC, Vasquez KM. Human XPC-hHR23B interacts with XPA-RPA in the recognition of triplex-directed psoralen DNA interstrand crosslinks. Nucleic Acids Res 33(9):2993-3001, 2005. PMCID: PMC1140082.
33. Wang G, Vasquez KM. Naturally occurring H-DNA-forming sequences are mutagenic in mammalian cells. Proc Natl Acad Sci U S A 101(37):13448-53, 9/2004. PMCID: PMC518777.
34. Christensen LA, Conti CJ, Fischer SM, Vasquez KM. Mutation frequencies in murine keratinocytes as a function of carcinogenic status. Mol Carcinog 40(2):122-33, 6/2004. PMID: 15170817.
35. Rogers FA, Vasquez KM, Egholm M, Glazer PM. Site-directed recombination via bifunctional PNA-DNA conjugates. Proc Natl Acad Sci U S A 99(26):16695-700, 12/2002. PMCID: PMC139206.
36. Vasquez KM, Christensen J, Li L, Finch RA, Glazer PM. Human XPA and RPA DNA repair proteins participate in specific recognition of triplex-induced helical distortions. Proc Natl Acad Sci U S A 99(9):5848-53, 4/2002. PMCID: PMC122865.
37. Vasquez KM, Dagle JM, Weeks DL, Glazer PM. Chromosome targeting at short polypurine sites by cationic triplex-forming oligonucleotides. J Biol Chem 276(42):38536-41, 10/2001. PMID: 11504712.
38. Vasquez KM, Marburger K, Intody Z, Wilson JH. Manipulating the mammalian genome by homologous recombination. Proc Natl Acad Sci U S A 98(15):8403-10, 7/2001. PMCID: PMC37450.
39. Datta HJ, Chan PP, Vasquez KM, Gupta RC, Glazer PM. Triplex-induced recombination in human cell-free extracts. Dependence on XPA and HsRad51. J Biol Chem 276(21):18018-23, 5/2001. PMID: 11278954.
40. Vasquez KM, Narayanan L, Glazer PM. Specific mutations induced by triplex-forming oligonucleotides in mice. Science 290(5491):530-3, 10/2000. PMID: 11039937.
41. Finch RA, Liu M, Grill SP, Rose WC, Loomis R, Vasquez KM, Cheng Y, Sartorelli AC. Triapine (3-aminopyridine-2-carboxaldehyde- thiosemicarbazone): A potent inhibitor of ribonucleotide reductase activity with broad spectrum antitumor activity. Biochem Pharmacol 59(8):983-91, 4/2000. PMID: 10692563.
42. Perkins BD, Wensel TG, Vasquez KM, Wilson JH. Psoralen photo-cross-linking by triplex-forming oligonucleotides at multiple sites in the human rhodopsin gene. Biochemistry 38(39):12850-9, 9/1999. PMID: 10504255.
43. Vasquez KM, Wang G, Havre PA, Glazer PM. Chromosomal mutations induced by triplex-forming oligonucleotides in mammalian cells. Nucleic Acids Res 27(4):1176-81, 2/1999. PMCID: PMC148300.
44. Perkins BD, Wilson JH, Wensel TG, Vasquez KM. Triplex targets in the human rhodopsin gene. Biochemistry 37(32):11315-22, 8/1998. PMID: 9698379.
45. Vasquez KM Wilson JH. Triplex-directed modification of genes and gene activity. Trends Biochem Sci 23(1):4-9, 1998. PMID: 9478127.
46. Vasquez KM, Wensel TG, Hogan ME, Wilson JH. High-efficiency triple-helix-mediated photo-cross-linking at a targeted site within a selectable mammalian gene. Biochemistry 35(33):10712-9, 8/1996. PMID: 8718860.
47. Vasquez KM, Wensel TG, Hogan ME, Wilson JH. High-affinity triple helix formation by synthetic oligonucleotides at a site within a selectable mammalian gene. Biochemistry 34(21):7243-51, 5/1995. PMID: 7766635.
48. Zendegui JG, Vasquez KM, Tinsley JH, Kessler DJ, Hogan ME. In vivo stability and kinetics of absorption and disposition of 3' phosphopropyl amine oligonucleotides. Nucleic Acids Res 20(2):307-14, 1/1992. PMCID: PMC310371.
49. Avery TL, Finch RA, Vasquez KM, Radparvar S, Hanna NB, Revankar GR, Robins RK. Chemotherapeutic characterization in mice of 2-amino-9-beta-D-ribofuranosylpurine-6-sulfinamide (sulfinosine), a novel purine nucleoside with unique antitumor properties. Cancer Res 50(9):2625-30, 5/1990. PMID: 2328488.
50. Finch RA, Vasquez KM, Hanna NB, Revankar GR, Robins RK, Avery TL. Oxidation of 2-amino-9-beta-D-ribofuranosylpurine-6-sulfenamide to the corresponding 6-sulfonamide facilitates changes in biologic characterization that include activity against thiopurine-refractory experimental leukemia. Cancer Lett 50(1):63-70, 4/1990. PMID: 2322928.
1. Vasquez KM, Wang G. The yin and yang of repair mechanisms in DNA structure-induced genetic instability.Mutat Res. 2013 Mar-Apr;743-744:118-31. doi: 10.1016/j.mrfmmm.2012.11.005. Epub 2012 Dec 3.
2. Cooper DN, Bacolla A, Férec C, Vasquez KM, Kehrer-Sawatzki H, Chen JM. On the sequence-directed nature of human gene mutation: the role of genomic architecture and the local DNA sequence environment in mediating gene mutations underlying human inherited disease. Hum Mutat. 2011 Oct;32(10):1075-99. doi: 10.1002/humu.21557. Epub 2011 Sep 2. Review.
3. Mukherjee A, Vasquez KM.Triplex technology in studies of DNA damage, DNA repair, and mutagenesis.Biochimie. 2011 Aug;93(8):1197-208. Epub 2011 Apr 11. Review.
4. Vasquez KM, Legerski RJ. DNA interstrand crosslinks: repair, cell signaling, and therapeutic implications.Environ Mol Mutagen. 2010 Jul;51(6):491-2.
5. Vasquez KM. Targeting and processing of site-specific DNA interstrand crosslinks. Environ Mol Mutagen. 2010 Mar 1. PMID: 201961332.
6. Lange SS, Vasquez KM. HMGB1: The jack-of-all-trades protein is a master DNA repair mechanic. Mol Carcinog 48(7):571-80, 7/2009. PMID: 19360789.
7. Wang G, Zhao J, Vasquez KM. Methods to determine DNA structural alterations and genetic instability. Methods 48(1):54-62, 5/2009. e-Pub 2/24/2009. PMCID: PMC2693251.
8. Vasquez KM, Hanawalt PC. Intrinsic genomic instability from naturally occurring DNA structures: An introduction to the special issue. Mol Carcinog 48(4):271-2, 4/2009. PMID: 19306307.
9. Wang G, Vasquez KM. Models for chromosomal replication-independent non-B DNA structure-induced genetic instability. Mol Carcinog 48(4):286-98, 1/2009. e-Pub 2009. PMID: 19123200.
10. Jain A, Wang G, Vasquez KM. DNA triple helices: biological consequences and therapeutic potential. Biochimie 90(8):1117-30, 8/2008. PMCID: PMCPMC2586808.
11. Wang G, Vasquez KM. Z-DNA, an active element in the genome. Front Biosci 12:4424-38, 2007. PMID: 17485386.
12. Wang G, Vasquez KM. Non-B DNA structure-induced genetic instability. Mutat Res 598(1-2):103-19, 6/2006. PMID: 16516932.
13. Reddy MC, Vasquez KM. Repair of genome destabilizing lesions. Radiat Res 164(4 Pt 1):345-56, 10/2005. PMID: 16187737.
14. Thoma BS, Vasquez KM. Critical DNA damage recognition functions of XPC-hHR23B and XPA-RPA in nucleotide excision repair. Mol Carcinog 38(1):1-13, 9/2003. PMID: 12949838.
15. Vasquez KM, Glazer PM. Triplex-forming oligonucleotides: principles and applications. Q Rev Biophys 35(1):89-107, 2/2002. PMID: 11997982.
16. Vasquez KM, Wilson JH. Triplex-directed site-specific genome modification. Methods Mol Biol 133:183-200, 2000. PMID: 10561839.