Jac A. Nickoloff, Ph.D.
Molecular Genetics and Microbiology
University of New Mexico HSC
915 Camino de Salud NE
Albuquerque, NM 87131
 
Office: CRF 127
Tel: (505) 272-6960
Fax: (505) 272-6029
E-mail: jnickoloff@salud.unm.edu

Keywords: Recombination, DNA repair, mismatch repair

Education and Honors:

1984, Ph.D., Biochemistry, University of Colorado; 1984-88, Postdoctoral Fellow, Scripps Clinic and Research Foundation; 1988-1990, Postdoctoral Fellow, Los Alamos National Laboratory.

Research Interests

Current research is focused on determining the molecular mechanisms of that maintain eukaryotic genome stability including homologous recombination and nonhomologous end-joining.  Both yeast and mammalian cell systems are employed in studies involving the induction, mechanisms, consequences, and genetic control of these DNA repair processes.  Homologous recombination is a fundamental biological process involved in many important cellular processes including DNA replication, gene regulation, DNA double-strand break repair, chromosome translocations, and antibody gene assembly.  There is strong evidence linking 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 and non-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.  We employ cell lines with known mutations in DNA repair genes, and we also investigate the genetic effects of overexpressing repair proteins.  By using site-specific nucleases expressed in vivo, we examine double-strand break repair in eukaryotic chromosomes at specific loci. 

Two new research directions are focused on chromatin regulation of DNA repair and a recently discovered human integrase called Metnase.  In collaboration with MGM faculty member Mary Ann Osley, we are investigating changes in chromatin structure near DNA double-strand breaks.  We are determining the protein factors that regulate these changes and the genetic consequences of mutations in genes that encode these factors.  Metnase evolved only 50 million years ago and is present in anthropoid primates but not lower primates or other vertebrates.  Metnase is a fusion of a SET (protein methylase) domain and a nuclease domain derived from the Mariner transposase family.  Metnase promotes random DNA integration and nonhomologous end-joining, and it also promotes chromosome decatenation through interactions with 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

Recent Publications

1.     Rasila, K.K., Corwin, L.K., Williamson, E.A., Oshige, M., Bailey, S.M., Lee, S.-H., Nickoloff, J.A., and Hromas, R. (2007) The human integrase and NHEJ protein Metnase interacts with Topoisomerase IIa and enhances chromosome decatenation (submitted to Mol. Cell).

2.     Wray, J., Liu, J., Nickoloff, J.A. and Shen, Z. (2007) Role for human RAD52 in the response to replication-dependent DNA damage (submitted to Mol. Cell. Biol.). 

3.     Pohl, T. and Nickoloff, J.A.  Rad51-independent double-strand break repair by gene conversion requires Rad52 but not Rad55, Rad57, or Dmc1 (in revision at Mol. Cell. Biol.). 

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

5.     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.

6.     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.

7.     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.

8.     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.

9.     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.

10.  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.

11.  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.

12.  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.

13.  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.

14.  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.

15.  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.

16.  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.

17.  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.

18.  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.

19.  Nickoloff, J.A. and Brenneman, M.A. (2004) In Waldman, A. S. (ed.), Genetic Recombination - Reviews and Protocols. Humana Press, Totowa, NJ, pp. 35-52.

20.  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.

21.  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.

22.  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.

23.  Winn, L.M., Kim, P.M. and Nickoloff, J.A. (2003) Oxidative stress-induced homologous recombination as a novel mechanism for phenytoin-initiated toxicity. J. Pharmacol. Exp. Ther., 306, 523-527.

24.  Allen, C., Miller, C.A. and Nickoloff, J.A. (2003) The mutagenic potential of a single DNA double-strand break is not influenced by transcription. DNA Repair, 2, 1147-1156.

25.  Allen, C., Halbrook, J. and Nickoloff, J.A. (2003) Interactive competition between homologous recombination and non-homologous end joining. Mol. Cancer Res., 1, 913-920.

26.  Palmer, S., Schildkraut, E., Lazarin, R., Nguyen, J. and Nickoloff, J.A. (2002) Gene conversion tracts in Saccharomyces cerevisiae can be extremely short and highly directional. Nucleic Acids Res., 31, 1164-1173.

27.  Kim, P.M., Paffett, K.S., Solinger, J.A., Heyer, W.-D. and Nickoloff, J.A. (2002) Spontaneous and double-strand break-induced recombination, and gene conversion tract lengths, are differentially affected by overexpression of wild-type or ATPase-defective yeast Rad54. Nucleic Acids Res., 30, 2727-2735.

28.  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.

29. Allen, C., Kurimasa, A., Brennemann, M.A., Chen, D.J. and Nickoloff, J.A. (2002) DNA-dependent protein kinase suppresses double-strand break-induced and spontaneous homologous recombination. Proc. Natl. Acad. Sci. USA, 99, 3758-3763.