The Role of the Putative DNA Sensor ZBP1 in Tumorigenesis

Department of Microbiology & Immunology Programme
Seminar Series … September 2014
Day / Date / Time:
16 September 2014
12.00pm – 1.00pm
The Role of the Putative DNA Sensor
ZBP1 in Tumorigenesis
Dr Stephan GASSER
CeLS Auditorium
Centre for Life Sciences,
Level 1, 28 Medical Drive
Singapore 117456
A/P Sylvie Alonso
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LSI Immunology Programme
Department of Microbiology
National University of Singapore
The DNA-binding protein ZBP1 (also called DAI or DLM1) was suggested to be a
sensor of DNA in the cytosol. However, the role of ZBP1 in cytosolic DNA
recognition is not well understood. Here we report that ZBP1 is involved in
sensing of DNA damage in tumor cells. Zbp1-deficiency increased the survival of
Eμ-Myc mice, a mouse model for Burkitt lymphomas. No apparent lymphomas
were observed in Zbp1-deficient Eμ-Myc mice that survived longer than
Zbp1+/+Eμ-Myc mice. Zbp1-deficient B-cell lymphoma cells expressed higher
levels of markers for DNA damage and the DNA damage response. The enhanced
DNA damage correlated with elevated levels of TNF-α and cleaved CASPASE 3,
7 and 8 in Zbp1-deficient tumor cells. Inhibition of the tumor suppressor ataxia
telangiectasia mutated (ATM), which controls cellular responses to DNA damage,
decreased the survival of Zbp1-deficient Eμ-Myc mice. Administration of blocking
TNF-α antibodies reversed the lower tumor load in Zbp1-/-Eμ-Myc mice. DLM1
or ZBP1 expression was upregulated and partially translocated to the nucleus in Bcell lymphoma of Eμ-Myc mice in response to DNA damage and in tumors of
chronic lymphocytic leukemia (CLL) patients. In summary, we show that ZBP1
deficiency promotes DNA damage in tumor cells and suppresses B-cell
lymphomagenesis in Eμ-Myc mice.
Recent Publications
Chwee J.Y., Lee S.K., Peiwen M.C.A. and Gasser S. (2014) Pam3CSK4
Synergizes with the Anticancer Effect of Ara-C in Mouse Non-Hodgkin
Lymphoma Cells. Clinical Cancer Res (in press).
Le Bert N., Lam A.R., Ho S.S.W., Shen Y.J., Liu M.M. and Gasser S. (2014)
Sting-dependent cytosolic DNA sensor pathways regulate NKG2D ligand
expression. OncoImmunology (in press).
Lam A.R., Le Bert N., Ho S.S.W., Shen Y.J., Tang L.F.M, Xiong, G.M., Croxford
J.L., Pan M.F., Huang C.W., Koo C.X., Ishii K.J., Akira S., Raulet D.H. and
Gasser S. (2014) RAE-1 ligands for the NKG2D receptor are regulated by STINGdependent DNA sensor pathways in lymphoma. Cancer Res. 74(8):2193-203.
Le Bert N. and Gasser S. (2014). Advances in NKG2D ligand recognition and
responses by NK cells. Immunol and Cell Biol. 92(3):230-6.