Role of Chk1 and the Fanconi anemia pathway in Myc-dependent tumorigenesis

• Applicant: Dr. Thomas Schleker
• Subject Area: Cell Biology
• Term: from 2010 to 2012
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 193989657

The transcription factor Myc, encoded by the c-myc oncogene, is frequently overexpressed and is a general driving force in cancer. High levels of Myc drive cellular proliferation, but at the same time elicit genotoxic stress during DNA replication, trigger a DNA damage response and, depending on the cellular context, induce apoptosis and/or senescence. The Chk1 kinase is a central effector of the replication checkpoint and is essential for cellular survival. As shown for other checkpoint proteins, Chk1 might conceivably act as a tumor suppressor, meaning that its depletion should accelerate tumorigenesis. On the other hand, maintaining minimal levels of Chk1 might be critical for tumor growth and/or survival. Here, I propose to address the role of Chk1 in Myc-induced lymphomagenesis, based on the study of E¿-myc transgenic mice carrying either a heterozygous knockout allele of the Chk1 gene, or an additional Chk1 transgene. I will undertake a systematic characterization of these mice at the genetic, cellular and molecular levels, at both the pre-tumoral and tumoral stages. In parallel, I will characterize the effects of Chk1 inhibition on lymphoma growth and/or survival, as well as upon Myc activation in primary mouse fibroblasts. As a complementary approach, I will aim to provide a whole-genome fingerprint of Myc-induced DNA damage by monitoring the occurrence of the DNA damage marker ¿-H2AX on chromatin, as well as to characterize to which extent the Chk1-interacting Fanconi Anemia pathway is required to maintain genome stability in Myc-overexpressing cells. This study should provide crucial insight on how inhibition of Chk1 or the Fanconi Anemia may be exploited for treatment of Myc-driven tumors.

• DFG Programme: Research Fellowships
• International Connection: Italy
• Host: Dr. Bruno Amati