- Andreas Bergthaler Group
- Christoph Binder Group
- Christoph Bock Group
- Sylvia Knapp Group
- Robert Kralovics Group
- Stefan Kubicek Group
- Joanna I. Loizou Group
- Jörg Menche Group
- Giulio Superti-Furga Group
- Georg Winter Group
- Chemical Screening, Proteomics and Metabolomics Facility
- Biomedical Sequencing Facility (BSF)
- Keiryn Bennett (Senior Researcher on Leave)
CeMM Principal Investigator
DNA Damage Signalling and Cancer
The repair of damaged DNA is stringently controlled to avoid the development of cancer and other diseases. As well as being caused by exogenous factors such as tobacco and UV, DNA damage in the form of double-strand breaks can also be caused during physiological processes including replicative stress, which occurs during intense cell proliferation, and somatic recombination in B and T immune cells, which is a critical part of the adaptive immune response.
We use mouse models and genomics approaches to understand the complex repair mechanisms of DNA double-strand breaks, and how this can breakdown and cause diseases such as leukemia.
DNA repair pathways in replicative stress
Cells have evolved complex signaling pathways to rapidly repair DNA damage and avoid cell death and genomic instability. These signaling cascades are triggered by DNA damage sensor proteins that activate the kinases ATM and/or ATR, which phosphorylate various target proteins. Downstream effectors then either repair the damage, halt the cell cycle to allow the damage to be repaired, or induce apoptosis if the damage is too severe.
We take an unbiased, genome-wide siRNA screening approach to identify proteins required for the response to DNA damage caused by replicative stress. We also use functional proteomics approaches including mass spectrometry and global phosphoproteomics to work out the mechanism of action of these proteins. We are also interested in their potential role in tumorigenesis. Our hypothesis is that cancerous cells require these DNA damage response proteins to deal with the increased replicative stress that occurs in rapidly dividing cancer cells. If this is the case, then they may be valuable targets for cancer treatment as inhibiting them could induce apoptosis.
Mechanisms of somatic recombination and the development of lymphomas
During the development of B and T lymphocytes, DNA breaks are generated in a programmed manner and repaired by somatic recombination to enable an efficient immune response. Failure to repair these DNA breaks efficiently leads to immunodeficiency and also predisposes to lymphomas. We are interested in understanding how the DNA breaks formed during somatic recombination are resolved, and how defective repair can cause cancer.
To address these questions, we use genetic mouse models as well as cells derived from patients with reciprocal lymphomas. The former models allow us to understand the biological roles of DNA repair proteins in vivo while the latter allow us to test the pathological findings of the mouse models.
Our aim is to shed light on what goes wrong during the development of immune deficiencies and B or T cell lymphomas.
Haploid genetic screens to identify interactions between DNA repair proteins and pathways
Human cells have evolved several highly complex pathways to repair DNA damage in order to maintain the fidelity of their genome. To identify genetic interactions between different DNA repair pathways and proteins, we are using the human haploid cell line KBM7.
By performing forward genetic screens in these human haploid cells we aim to identify gene-gene interactions that confer ‘cellular fitness’ following DNA damage. The identification of such interactions will allow us to determine how the DNA repair pathways collaborate to mount an effective response.
Joanna Loizou received her Ph.D. at the University of Manchester and Sussex with Keith Caldecott, and carried out post-doctoral research at the International Agency for Research on Cancer, Lyon, France with Zhao-Qi Wang and Zdenko Herceg and later at the London Research Institute, CRUK, England with Axel Behrens. She joined CeMM in 2011.
Zhang T, et al. Competition between NBS1 and ATMIN controls ATM signaling pathway choice. 2012 Dec 27;2(6):1498-504. doi: 10.1016/j.celrep.2012.11.002. Epub 2012 Dec 6. (abstract)
Loizou JI, et al. ATMIN is required for maintenance of genomic stability and suppression of B cell lymphoma. Cancer Cell. 2011 May 17;19(5):587-600. doi: 10.1016/j.ccr.2011.03.022. (abstract)
Loizou JI, et al. Histone acetyltransferase cofactor Trrap is essential for maintaining the hematopoietic stem/progenitor cell pool. 2009 Nov 15;183(10):6422-31. doi: 10.4049/jimmunol.0901969. Epub 2009 Oct 30. (abstract)
Loizou JI, et al. Epigenetic information in chromatin: the code of entry for DNA repair. Cell Cycle. 2006 Apr;5(7):696-701. Epub 2006 Apr 1. Review. (abstract)
Murr R*, Loizou JI*, et al. Histone acetylation by Trrap-Tip60 modulates loading of repair proteins and repair of DNA double-strand breaks. Nat Cell Biol. 2006 Jan;8(1):91-9. Epub 2005 Dec 11. *equal contribution (abstract)
Loizou JI, et al. The protein kinase CK2 facilitates repair of chromosomal DNA single-strand breaks. Cell. 2004 Apr 2;117(1):17-28. (abstract)
Iftner T, et al. Interference of papillomavirus E6 protein with single-strand break repair by interaction with XRCC1. EMBO J. 2002 Sep 2;21(17):4741-8. (abstract)