Jac A. Nickoloff , Ph.D.
Department Head and Professor

Phone: (970) 491-6674
Fax: (970) 491-0623
Email: J.Nickoloff@colostate.edu
Office: 433 Molecular and Radiological Biosciences Building

Degrees

• Ph.D., Biochemistry, University of Colorado
• B.A., Biochemistry, University of California, Santa Barbara

Research Interests

Dr. Nickoloff’s research is focused on cellular processes that maintain eukaryotic genome stability, including homologous recombination, nonhomologous end-joining and other DNA repair processes. Both yeast and mammalian cell systems are employed in studies involving the induction, mechanisms, consequences, and genetic control of DNA repair processes. Homologous recombination is has roles in key cellular processes including DNA replication, gene regulation, DNA double-strand break repair, chromosome translocations, and antibody gene assembly. Strong evidence links genetic recombination and other DNA repair processes to cancer initiation and progression. DNA damage stimulates recombination that is potentially mutagenic or carcinogenic. Studies are aimed at understanding the genetic consequences of DNA double-strand breaks and other DNA lesions, such as those caused by UV light and chemical agents, as well as the mechanisms and genetic consequences of delayed genomic instability induced by low-doses of ionizing radiation. During homologous recombination, mismatches are formed in heteroduplex DNA and our studies are also focused on mismatch repair. Mismatch repair systems play key roles in mutation and cancer avoidance.

Two new research directions are focused on chromatin regulation of DNA repair and a recently discovered human integrase called Metnase. We are investigating changes in chromatin structure near DNA double-strand breaks and the protein factors that regulate these changes. Metnase is a recently evolved human fusion protein that promotes random DNA integration and nonhomologous end-joining, and it stimulates chromosome decatenation by Topoisomerase IIα. We are currently testing whether manipulating Metnase levels or activity can be used to enhance homology-directed gene targeting in human cells. These studies may lead to more efficient and safer human gene therapy protocols. Metnase may also be an important factor in Topoisomerase IIα-mediated chromosome translocations that cause secondary tumors in patients treated with chemotherapeutics that inhibit Topoisomerase IIα.

Selected Publications

• De Haro, L.P., Wray, J., Williamson, E.A., Durant, S.T., Corwin, L., Gentry, A.C., Osheroff, N., Lee, S.-K., Hromas, R., and Nickoloff, J.A.  (2010)  Metnase promotes restart of stalled and collapsed replication forks.  Nucleic Acids Res. (in press).

• Wray, J., Williamson, E.A., Farrington, J., Chester, S., Kwan, L., Weinstock, D., Jasin, M., Lee, S.-H., Nickoloff, J.A., and Hromas, R.  (2010)  The transposase domain protein Metnase/SETMAR suppresses chromosomal translocations.  Cancer Genet. Cytogenet. 200, 184-190.  

• Shaheen, M., Williamson, E., Nickoloff, J., Lee, S.-H., Hromas, R.  (2010) Metnase/SETMAR: a domesticated primate transposase that enhances DNA repair, replication, and decatenation.  Genetica 138, 559–566.

• Shrivastav, M., Miller, C.A., De Haro, L.P., Durant, S.T., Chen, B.P.C., Chen, D.J., and Nickoloff, J.A. (2009)  DNA-PKcs and ATM co-regulate DNA double-strand break repair.  DNA Repair 8, 920-929.

• Wray, J., Williamson, E.A., Fnu, S., Lee, S.-H., Libby, E., Willman, C.L., Nickoloff, J.A., and Hromas, R. (2009)  Metnase mediates chromosome decatenation in acute leukemia cells.  Blood 114, 1852-1858.

• Tsukuda, T., Lo, Y.-C. (co-first authors), Krishna, S., Sterk, R., Osley, M.A., and Nickoloff, J.A. (2009) INO80-dependent chromatin remodeling optimizes DNA double-strand break repair by homologous recombination.  DNA Repair 8, 360–369.   

• Wray, J., Williamson, E.A., Royce, M., Shaheen, M., Beck, B.D., Lee, S.-H., Nickoloff, J., and Hromas, R. (2009)  Metnase mediates resistance to topoisomerase II inhibitors in breast cancer cells.  PLoSONE 4 (4), e5323.

• Hromas, R., Lee, S.-H., Oshige, M., Martinez, L., Farrington, J., Kwan Corwin, L., Ramsey, H., Nickoloff, J.A., Williamson, E.A. (2008) The human SET and transposase domain protein Metnase interacts with DNA ligase IV and enhances the efficiency and accuracy of non-homologous end joining.  DNA Repair 7, 1927-1937.  

• Williamson, E., Rasila, K.K., Corwin, L.K., Wray, J., Beck, B.D., Severns, V., Mobarak, C., Lee, S.-H., Nickoloff, J.A., and Hromas, R. (2008) The SET and transposase domain protein Metnase enhances chromosome decatenation:  Regulation by automethylation.  Nucleic Acids Res. 36, 5822-5831.

• Williamson, E.A., Farrington, J., Martinez, L., Nickoloff, J., Ness, S., O’Rourke, J. Lee, S.-H., Hromas, R. (2008) Expression levels of the human DNA repair protein Metnase influence lentiviral genomic integration.  Biochemie 90, 1422-1426.  

• Nickoloff, J.A., De Haro, L.P., Wray, J., and Hromas, R. (2008) Mechanisms of leukemia translocations.  Curr. Opin. Hematol. 15, 338-345.

• Hromas, R., Lee, S.-H., Oshige, M., Martinez, L., Farrington, J., Kwan Corwin, L., Ramsey, H., Nickoloff, J.A., Williamson, E.A. (2008) The human SET and transposase domain protein Metnase interacts with DNA ligase IV and enhances the efficiency and accuracy of non-homologous end joining. DNA Repair (in press).

• Williamson, E., Rasila, K.K., Corwin, L.K., Wray, J., Beck, B.D., Severns, V., Mobarak, C., Lee, S.-H., Nickoloff, J.A., and Hromas, R. (2008) The SET and transposase domain protein Metnase enhances chromosome decatenation: Regulation by automethylation. Nucleic Acids Res. (in press).

• Wray, J., Liu, J., Nickoloff, J.A., Shen, Z. (2008) Distinct RAD51 associations with RAD52 and BCCIP in response to DNA damage and replication stress. Cancer Res. 68, 2699-2707.

• Williamson, E.A., Farrington, J., Martinez, L., Nickoloff, J., Ness, S., O’Rourke, J. Lee, S.-H., Hromas, R. (2008) Expression levels of the human DNA repair protein Metnase influence lentiviral genomic integration. Biochemie 90, 1422-1426.

• Pohl, T. and Nickoloff, J.A. Rad51-independent double-strand break repair by gene conversion requires Rad52 but not Rad55, Rad57, or Dmc1 Mol. Cell. Biol. 28, 897-906.

• Osley, M.A., Tsukuda, T. and Nickoloff, J.A. (2007) ATP-dependent chromatin remodeling factors and DNA damage repair. Mutat. Res., 618, 65-80.

• Krishna, S., Wagener, B.M., Liu, H.P., Lo, Y.-C., Sterk, R., Petrini, J.H.J. and Nickoloff, J.A. (2007) Mre11 and Ku regulation of double-strand break repair by gene conversion and break-induced replication. DNA Repair, 6, 797-808.

• Schildkraut, E., Miller, C.A. and Nickoloff, J.A. (2006) Transcription enhances donor use during double-strand break-induced gene conversion in human cells. Mol. Cell. Biol., 26, 3098-3105.

• Lo, Y.-C., Paffett, K.S., Amit, O., Clikeman, J.A., Sterk, R., Brenneman, M.A. and Nickoloff, J.A. (2006) Sgs1 regulates gene conversion tract lengths and crossovers independently of its helicase activity. Mol. Cell. Biol., 26, 4086-4094.

• Huang, L., Kim, P.M., Nickoloff, J.A. and Morgan, W.F. (2006) Targeted and non-targeted effects of low-dose ionizing radiation on delayed genomic instability in human cells. Cancer Res., 67, 1099-1104.

• Durant, S.T., Paffett, K.S., Shrivastav, M., Timmins, G.S., Morgan, W.F. and Nickoloff, J.A.(2006) UV radiation induces delayed hyperrecombination associated with hypermutation in human cells. Mol. Cell. Biol., 26, 6047-6055.

• Tsukuda, T., Fleming, A.B., Nickoloff, J.A. and Osley, M.A. (2005) Chromatin remodeling at a DNA double-strand break site in Saccharomyces cerevisiae. Nature, 438, 379-383.

• Schildkraut, E., Miller, C.A. and Nickoloff, J.A. (2005) Gene conversion and deletion frequencies during double-strand break repair in human cells are controlled by the distance between direct repeats. Nucleic Acids Res., 33, 1574-1580.

• Paffett, K.S., Clikeman, J.A., Palmer, S. and Nickoloff, J.A. (2005) Overexpression of Rad51 inhibits double-strand break-induced homologous recombination but does not affect gene conversion tract lengths. DNA Repair, 4, 687-698.

• Lu, H., Guo, X., Meng, X., Liu, J., Wray, J., Allen, C., Nickoloff, J.A. and Shen, Z. (2005) The BRCA2-interacting protein BCCIP functions in RAD51 and BRCA2 focus formation and homologous recombinational repair. Mol. Cell. Biol., 25, 1949-1957.

• Lo, Y.-C., Kurtz, R.B. and Nickoloff, J.A. (2005) Analysis of chromosome/allele loss in genetically unstable yeast by quantitative real-time PCR. Biotechniques, 38, 685-690.

• Lee, S.H., Oshige, M., Durant, S.T., Rasila, K.K., Williamson, E.A., Ramsey, H., Kwan, L., Nickoloff, J.A. and Hromas, R. (2005) The SET domain protein Metnase mediates foreign DNA integration and links integration to nonhomologous end-joining repair. Proc. Natl. Acad. Sci. USA, 102, 18075-18080.

• Durant, S.T. and Nickoloff, J.A. (2005) Good timing in the cell cycle for precise DNA repair by BRCA1. Cell Cycle, 4, 1216-1222.

• Convery, E., Shin, E.K., Ding, Q., Wang, W., Douglas, P., Nickoloff, J.A., Lees-Miller, S. and Meek, K. (2005) Inhibition of homologous recombination by variants of the catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs). Proc. Natl. Acad. Sci. USA, 102, 1345-1350.

• Wang, H., Boecker, W., Wang, H., Wang, X., Guan, J., Thompson, L.H., Nickoloff, J.A. and Iliakis, G. (2004) Caffeine inhibits homology directed repair of I-SceI induced DNA double-strand breaks. Oncogene, 23, 824-834.

• Miller, C.A., Bill, C.A. and Nickoloff, J.A. (2004) Characterization of palindromic loop mismatch repair tracts in mammalian cells. DNA Repair, 3, 421-428.

• Huang, L., Grimm, S., Smith, L.E., Kim, P.M., Nickoloff, J.A., Goloubeva, O.G. and Morgan, W.F. (2004) Ionizing radiation induces delayed hyperrecombination in mammalian cells. Mol. Cell. Biol., 24, 5060-5068.

• Bailey, S.M., Brenneman, M.A., Halbrook, J., Nickoloff, J.A., Ullrich, R.L. and Goodwin, E.H. (2004) The kinase activity of DNA-PK is required to protect mammalian telomeres. DNA Repair, 3, 225-233.

• Brenneman, M.A., Wagener, B.M., Miller, C.A., Allen, C. and Nickoloff, J.A. (2002) XRCC3 controls the fidelity of homologous recombination: roles for XRCC3 in late stages of recombination. Mol. Cell, 10, 387-395.

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