Signal Transduction

Staff
Funding
Student Projects
Key Recent Publications
Go to Glossary

Lab Head: Professor Kum Kum Khanna
kumkumK@qimr.edu.au

Our group is interested in understanding cellular responses to DNA damage. DNA damage occurs fairly regularly in all of us as a result of environmental factors such as increased exposure to DNA damaging agents or from genetic factors such as decreased efficiency of normal DNA repair processes. In any organism, the capacity to sense and respond to DNA damage is vital for maintaining healthy functioning cells. Deficiencies in the ability of cells to sense and repair damage leads to neurodegeneration, immune deficiency, infertility and aging. This area is also of critical importance to cancer research as the pathway controlling the DNA damage response are involved in tumor suppression and are believed to be mutated at the early stage in the evolution of cancer.

Several genes involved in the DNA damage response pathways eg ATM, BRCA1, BRCA2, CHK2 and p53 contribute to breast cancers and underlying theme of our research program is to identify other known or novel genes in these pathways which might have similar involvement in cancer susceptibility by preventing the generation of mutations in our DNA. Over the past three years, research in the lab has diversified to encompass proteins that signal the presence of DNA damage to DNA repair, transcription and cell cycle control machineries (see publications list below). We are also interested in understanding how the defective DNA damage response might predispose women to breast cancer. Current work includes continued analysis of known and novel DNA repair and cell cycle control proteins and to study their mechanism of action and link with cancer susceptibility. Towards this end, we are using a broad range of techniques and approaches in mammalian cells.

Back to Top

Staff

Funding

We gratefully acknowledge financial support of:
National Health Medical Research Council
Australian Research Council
The Queensland Cancer Fund
Komen Breast Cancer Foundation (US)
US Department of Defense

Key Publications

K.K. Khanna, Queensland Institute of Medical Research, Herston, QLD, Australia; Y. Shiloh, Tel Aviv University, Tel Aviv, Israel (Eds.) The DNA Damage Response: Implications on Cancer Formation and Treatment. http://www.springer.com/978-90-481-2560-9

Khanna, K.K., Shafman, T., Kedar, P., Yen, T., Spring, K., Gatei, M., Zhang, N., Watters, D., Egerton, M., Shiloh, Y. And Lavin, M.F. Role of the ATM protein in Stress response to DNA damage: evidence for interaction with c-Abl. Nature (1997) 386, 520-523.

Khanna, K.K., Gatti, R., Concannon, P., Weemaes, C.M.R., Hoekstra, M.F., Lavin,. M.F. and Andrea, A. (1998) Cellular response to DNA damage and human chromosome instability syndromes. In: DNA damage repair: DNA repair in higher eukaryotes, Eds. Nickoloff, J.A. and Hoekstra, M.F. pp395-441. Humana Press Inc. Totowa, N.J.

Zhang, N., Chen, P., Gatei, M., Scott, S., Khanna, K.K. and Lavin, M.F. (1998) An anti-sense construct of full-length ATM cDNA imposes a radiosensitive phenotype on normal cells. Oncogene 17: 811-818.

Khanna, K. K., Keating K. E., Kozlov, S., Scott, S., Maqtouf, G., Hobson, K., Taya, T., Gabrielli, B., Chan, D., Miller, S. P. and Lavin, M. F. ATM associates with and phosphorylates p53: mapping the region of interaction. Nat Genet (1998) 20: 398-400.

Imyanitov, E.N., Birrell, G.W., Fillipovich, I., Sorokina N., Arnold, J., Mould, M.A., Wright, K., Walsh, M., Mok, S.C., Lavin, M.F., Chenevix-Trench, G and Khanna, K.K. Frequent loss of heterozygosity at 1p36 in ovarian adenocarcinomas but the gene encoding p73 is unlikely to be the target. Oncogene (1999) 18: 4640-2.

Lavin, M.F. and Khanna, K.K. The ATM gene and stress response. In DNA Recombination and Repair, Eds Smith P.J & Jones C.J. pp166-201, Oxford University Press Inc, New York.

Lavin, M.F. and Khanna, K.K. ATM: the protein encoded by gene mutated in the radiosensitive syndrome ataxia-telangiectasia. International Journal of Radiation Biology (1999) 75(10):1201-14.

Khanna, K.K. ATM gene and Cancer Risk: A continuing debate. J. Natl. Cancer I. (2000), 92 (10), 795-802)

Zhou, B.B., Chaturvedi, P., Spring, K., Scott, S., Johanson, R.A., Mishra, R., Mattern, M.R., Winkler, J.D. and Khanna, K.K. Caffeine Abolishes the Mammalian G2/M DNA Damage Checkpoint by Inhibiting Ataxia-Telangiectasia Mutated Kinase Activity. J. Biol. Chem. (2000) 275: 10342-10348.

Gatei M, Young D, Cerosaletti K, Desei-Mehta A, Spring K, Kozlov S, Lavin MF, Gatti R, Concannon P, Khanna KK. ATM dependent phosphorylation of nibrin in response to radiation exposure. Nature Genet. (2000) May 1; 25:115-119.

Gatei M, Scott S, Fillipovitch I, Soronika K, Lavin MF, Weber B, Khanna KK. Role of ATM in DNA-damage induced phosphorylation of BRCA1. Cancer Research (2000) 60:3299-3304

Fillippovich, I., Sorokina , N., Gatei, M, Haupt, Y., Hobson K., Moallem, E., Mould, M., McGuicin M., Lavin, M.F. and Khanna, K.K. Transactivation-deficient p73alpha (p73Dexon2) inibits apoptosis and competes with p53. Oncogene (2001), 20: 514-522.

Gatei M, Zhou BB, Hobson K, Shaun S, Young D and Khanna, K.K. ATM and ATR phosphorylates distinct and overlapping sites on Brca1: in vivo assessment using phospho-specific antibodies manner. J. Biol. Chem 2001, 276: 17276-17280.

Khanna, K.K. and Jackson, S.P. Double strand break repair: signalling, repair and the connection. Nature Genetics 2001, 27: 247-254.

Khanna K.K., Lavin, M.F., Jackson, S.P. and Mulhern, T. ATM, a central regulator of cellular responses to DNA damage. Cell Death and Differen. (2001), Nov;8(11):1052-65.

Chenevix-Trench, G., Spurdle, A.B., Gatei, M., Kelly, H., Marsh, A., Chen, X., Donn,K., Cummings,M., Nyholt,D., Jenkins, M.A., Scott,C., Pupo, G.M., Dork, T., Bendix, R., Kirk, J., Tucker, K., McCredie, MRE., Hopper, J.L., Sambrook, J., Mann, G.J. and Khanna, K.K. Dominant negative ATM mutations in breast cancer families. J. Natl. Cancer Inst., 2002, 94: 205-15.

Gatei, M., Sloper, K., Sorensen, C., Syljuasen, R., Jacob, F., Hobson, K., Savage, K., Lukas, J., Bin-Bing, Z., Bartek, J. and Khanna, K.K. ATM and NBS1 dependent phosphorylation of CHK1 on S317 in response to IR. J. Biol. Chem. 2003, 278(17): 14806-11.

Khanna, K.K. and Tibbetts R. DNA damage response. In Encyclopedia of the Human Genome (2003) Nature Publishing group. Vol.2, pp.74-80. Cooper DN (ed.), www.ehgonline.com.

Krause, D.R, Jonnalagadda, J.C, Gatei M.H, Sillje H.HW, Zhou BB, Nigg EA, and Khanna, K.K. Suppression of Tousled like kinase after DNA damage or replication block requires ATM, NBS1 and CHK1. Oncogene 2003, 22: 5927-5937.

Goodarzi, A.A., Jonnalagadda, J.C., Douglas, P., Ruiqiong Ye, Moorhead, G.B.G., Lees-Miller S.P. and Khanna, K.K. Autophosphorylation of Ataxia-telangiectasia mutated (ATM) is regulated by protein phosphatase 2A. EMBO J, Nov 2004, 23:4451-61.

Young, D.B., Jonnalagadda, J., Gatei, M, Jans, DA., Meyn, S and Khanna, K.K. Identifying domains of ATM required for nuclear localisation and association with chromatin. J. Biol. Chem. 2005 ,280: 27587-94.

Fabbro, M., Zhou, B.B., Takahashi, M., Sarcevic, B., Lal, P., Graham, M.E., Robinson, P.J., Nigg, E.A., Ono, Y and Khanna, K.K. CDK1, ERK and PLK co-operate to phosphorylate a novel protein, Cep55, required for cytokinesis. Development Cell, Oct 2005, 9: 477-488.

Papp, L.V., Lu, J., Striebel, F., Kennedy, D., Holmgren, A. and Khanna, K.K. Redox state of SECIS binding protein 2 controls its localization and selenocysteine incorporation function. Mol. Cell. Biol. 2006 ; 26(13) :4895-910.

Pagan J.K., Arnold, J., Hanchard, K.J., Kumar, R., Bruno,T., Jones, M. J., Richard, D.J., Forrest, A., Spurdle, A., Verdin, E., Crossley, M., Fanciulli, M, Chenevix-Trench, G., Young, D.B. and Khanna, K. K. A novel co-repressor represses transcription through an interaction with CTBP. J Biol Chem. 2007, 282 (20): 15248-57.

Richard, D., Bolderson, E., Cubeddu, L., Wadsworth, R.I., Savage, K.,Sharma, G.G., Nicolette, M.L., Tsvetnov, S., McIlwraith, M.J., Pandita, R.,Takeda, S., Hay, R.T., Gautier., J., West, S.C., Paull, T., Pandita, T.K.,White, M.F. and Khanna, K.K (2008). Evolutionary conserved single stranded DNA binding protein 'hSSB1' is critical for genomic stability. Nature, Advance online publication 30th April 2008, 453:677-81.

Papp LV, Wang J, Kennedy D, Boucher D, Zhang Y, Gladyshev VN, Singh RN, Khanna KK. Functional characterization of alternatively spliced human SECISBP2 transcript variants. Nucleic Acids Res. 2008 Dec;36(22):7192-206.

Van der Horst and Khanna, K.K. The peptidyl-prolyl isomerase Pin1 regulates cytokinesis through Cep55. Cancer Research 2009, 69(16):6651-9.

Fabbro, F., Oakes, V., Graham, M.E., Smith, C.M., Ma, M.P.C., Robinson, P.J. and Khanna, K.K. The actin-binding and bundling protein, Eplin, is required for cytokinesis. Cell Cycle 2009 Mar 1;8(5):757-64

Richard DJ, Bolderson E, Khanna KK. Multiple human single-stranded DNA binding proteins function in genome maintenance: structural, biochemical and functional analysis. Crit Rev Biochem Mol Biol. 2009 Apr 14:1-19.

Bolderson, E., Richard, D., Edelmann, W. and Khanna, K.K. Involvement of repair nuclease, Exo 1b, in DNA damage-induced apoptosis. Nuclear Acid Research2009 Jun;37(10):3452-63.

Li Y, Bolderson E, Kumar R, Muniandy PA, Xue Y, Richard DJ, Seidman M, Pandita TK, Khanna K.K., Wang W. hSSB1 and hSSB2 form similar multiprotein complexes that participate in DNA damage response. J Biol Chem. 2009 Aug 28;284(35):23525-31

Skaar, J.R., Richard, D.J., Saraf, A., Toschi, A., Bolderson, E., Florens, L., Washburn, MP., Khanna, K.K., Pagano, M. INTS3 controls the hSSB1-mediated DNA damage response. J. Cell Biol. 2009, 187(1):25-32.

Bolderson, E., Richard, D., and Khanna, K.K.  DNA damage response and genome stability: implications for cancer treatment. Clinical Cancer Research, 2009,15(20):6314-20.

Papp LV, Lu J, Bolderson E, Boucher D, Singh R, Holmgren A, Khanna KK. SECIS binding protein 2 promotes cell survival by protecting against oxidative stress.
Antioxid Redox Signal. 2009 Nov 11. [Epub ahead of print]

Bolderson E, Tomimatsu N, Richard DJ, Boucher D, Kumar R, Pandita TK, Burma S, Khanna KK. Phosphorylation of Exo-1 modulates homologous recombination repair of double-strand breaks. Nucleic Acids Res. 2009 Dec 17. [Epub ahead of print]

Back to Top