Department of Pharmacology & Chemical Biology at the University of Pittsburgh
Christopher Bakkenist, PhD
Associate Professor, Radiation Oncology
Hillman Cancer Center 2.6
5117 Centre Avenue, Pittsburgh, PA 15232

Phone: 412-623-7765

Fax: 412-623-7761


BSc (Hons), Biochemistry/Chemistry, University of Liverpool, UK, 1989. PhD Imperial College, University of London, UK, 1994. Postdoctoral Fellow, St. Jude Children's Research Hospital, Memphis, TN, 1999-2005.

Research Areas
Cancer Pharmacology
DNA Repair
Photo of Christopher Bakkenist, PhD

ATM physically and functionally interacts with PCNA to regulate DNA synthesis (Archived seminar from NIH DNA Repair Interest Group videoconference - February 21, 2012)

Two principal signaling pathways are activated by DNA damage. While ATM kinase is activated by double-stranded DNA breaks (DSBs), ATR kinase is induced by single-stranded DNA (ssDNA) gaps. However, crosstalk exists between the pathways, and most DNA damaging agents activate both. Further, ATM and ATR phosphorylate an overlapping set of substrates that promote cell cycle arrest and DNA repair. As such, the indispensable ATM kinase signaling that ensures cell survival and chromosome stability is not well understood. Nevertheless, since ataxia telangiectasia (A-T) patients that express no ATM protein are the most radiosensitive humans, ATM kinase inhibitors are being developed as radiosensitizing agents.
In order to identify indispensable ATM kinase signaling, we developed the use of two selective and reversible ATM kinase inhibitors as “molecular switches” to transiently inhibit ATM kinase activity in cells. Using this innovative approach, we discovered that acute ATM kinase inhibition abrogates ionizing radiation (IR)- and topoisomerase 1 poison-induced sister chromatid exchange (SCE), a phenotype attributed to the repair of damaged DNA replication forks via homologous recombination. Since DNA damage-induced SCE was maintained in A-T cells that express no ATM protein, and the ATM kinase inhibitors had no effect on DNA damage-induced SCE in A-T cells, these data revealed, for the first time, that the consequences of acute ATM kinase inhibition (ATM kinase inhibition for a 1 h interval) and adaptation to ATM protein disruption are distinct. These data were published as an article in Science Signaling.


ATM kinase inhibitors impede sister chromatid exchanges (arrows) which are believed to be a cytological manifestation of recombination repair at the replication fork.

This work is significant in so far as ATM kinase inhibitors have the potential to treat tens of thousands of lung and pancreatic cancers with acquired mutations in p53 and the Fanconi anemia pathway as well as many other cancers that experience replication stress as a consequence of acquired mutations every year. Lung and pancreatic cancers are among the most lethal cancers with 5-year survival rates of just 15% and 4%, respectively. The NCI estimates that 196,130 deaths were caused by lung and pancreatic cancer in the USA alone in 2008. Current therapies are not effective and there is a desperate need for novel and rational treatments for these cancers. Yet despite the great strides that have been made in identifying mutations in these cancers, no rational therapies exploiting these genetic defects have been developed. We propose that ATM kinase inhibitors have the potential to kill cancer cells that experience replication stress as a consequence of acquired mutations.
Many cancer cells acquire a defect in a DNA repair pathway during tumor development. Such defects promote the additional changes that are required for most normal cells to become malignant. As a result, the multiplicity of DNA repair pathways available in normal cells is often not available in cancer cells, a difference that can be exploited for the selective killing of cancer cells. For example, the Fanconi anemia (FA) pathway is mutated in >10% of pancreatic cancers, and >15% of lung cancers have inactivated FANCF. The FA pathway has an established role in the repair of stalled and collapsed replication forks. Fancg-/-atm-/- mice are nonviable and ATM disruption induces cell death in FANCG-/- fibroblasts. ATM kinase inhibition using KU55933 has also been shown to kill FA-deficient pancreatic tumor cell lines. We propose that ATM kinase promotes the repair of damaged replication forks in a pathway that functions in parallel to the FA pathway, and is therefore essential for the viability of lung and pancreatic cancer cells that are defective in FA proteins.


Important Publications
Choi S, Srivas R, Fu KY, Hood BL, Dost B, Gibson GA, Watkins SC, Van Houten B, Bandeira N, Conrads TP, Ideker T and Bakkenist CJ.  (2012) Quantitative proteomics reveals ATM kinase-dependent exchange in DNA damage response complexes.  Journal of Proteome Research, advance online publication
Gamper AM, Choi S, Matsumoto M, Banerjee D, Tomkinson AE and Bakkenist CJ.  (2012)  ATM physically and functionally interacts with PCNA to regulate DNA synthesis.  Journal of Biological Chemistry 287:12445-12454.
Choi S, Toledo LI, Fernandez-Capetillo O and Bakkenist CJ.  (2011)  CGK733 does not inhibit ATM or ATR kinase activity in H460 human lung cancer cells.  DNA Repair 10:1000-1001
White JS, Yue N, Hu J, Bakkenist CJ.  (2011)  The ATM kinase signaling induced by the low-energy ß-particles emitted by 33P is essential for the suppression of chromosome aberrations and is greater than that induced by the energetic ß-particles emitted by 32P.  Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis, 708, 28-36

Choi S, Gamper A, White JS, Bakkenist CJ.  (2010)  Inhibition of ATM kinase activity does not phenocopy ATM protein disruption: implications for the clinical utility of ATM kinase inhibitors. Cell Cycle 9: 4052-4057

White JS, Choi S, Bakkenist CJ.  (2010)  Transient ATM kinase inhibition disrupts DNA damage-induced sister chromatid exchange.  Science Signaling 3: ra44

Bakkenist CJ, Kastan MB.  (2004)  Initiating Cellular Stress Responses. Cell 118: 9-17

Bakkenist CJ, Kastan MB.  (2003)  DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation.  Nature 421: 499-506

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