Signal Transduction

Lyndell Kelly Staff
Funding
Key Recent Publications
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Lab Head: Dr Kum Kum Khanna
kumkumK@qimr.edu.au

cartoon: DNA damage and repair 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.

Staff

Labhead:	Dr Kum Kum Khanna
Other Staff:	Derek Richard Aaron Urquhart Karen Hobson Emma Bolderson Julia Pagan Masroor Shariff Armando Van der Horst Didier Boucher Jessie Kelly Mathew Jones Amanda Bains

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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

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.