- Kaan Boztug (Director LBI-RUD)
- Thijn Brummelkamp (CeMM)
- Robert Kralovics Group (CeMM)
- Joanna I. Loizou Group (CeMM)
- Nuno Maulide (CeMM)
- Jörg Menche Group
- Vanja Nagy (LBI-RUD)
- Thomas Reiberger (LBI-RUD/CeMM)
- Georg Stary (LBI-RUD/CeMM)
- Miriam Unterlass (CeMM)
- Andreas Villunger (CeMM/LBI-RUD)
CeMM Adjunct Principal Investigator
DNA Damage Signalling and Cancer
The human genome is constantly exposed to endogenous and exogenous sources of DNA damage. DNA repair ensures the integrity of large eukaryotic genomes by minimising the mutation rate. We are interested in exploring the several highly effective pathways for DNA repair that have distinct specificities, and are evolutionary conserved despite partial redundancies. While somatic defects in DNA repair genes contribute to cancer and other severe diseases, germline mutations in relevant DNA repair genes cause specific deficiencies which are the underlying cause for a family of rare diseases. We are investigating the genetic interactions of the intricate crosstalk between DNA damage and repair mechanisms with the ultimate goal that this may pave the way to rational therapeutic approaches.
Consequences of DNA damage and repair on genomic mutation signatures
The compilation of somatic mutations is the outcome of one or more mutational processes that have been operative due to DNA damage and repair processes. The resulting mutational signature is determined by the intensity and duration of exposure to each mutational process. We seek to systematically map the contribution of various DNA damage and repair processes to the generation of mutation signatures hence deciphering the contribution of genetic and environmental sources to genome stability.
Synthetic lethal and viable interactions
Complex interactions between different genes have been a focus of genetic research on model organisms for decades. The concepts of synthetic lethality and synthetic viability have been extensively explored because defects in a specific cellular pathway may (de)sensitize cells for the loss of another. Using genome-scale approaches, including CRISPR screens, we aim to identify new therapeutic targets, at scale, to ameliorate pathologies. Our hypothesis is that through the exploration of genetic, proteomic and chemical space will identify novel regulatory pathways for DNA repair.
Repair of CRISPR-Cas9 generated DNA breaks
Repair of DNA double-strand breaks is thought to occur mainly via two major pathways: error-prone non-homologous and joining (NHEJ) and error-free homologous recombination (HR). An enzyme that generates DNA double strand breaks, and is extensively used to promote gene editing, is Cas9. While large efforts have gone into the utilization of CRISPR-Cas9 for gene editing purposes, comparatively little advancement has been made with regard to the cellular mechanisms by which DNA lesions generated by Cas9 are dealt with. We are interested in understanding the contribution of DNA repair pathways to the resolution of DNA double-strand breaks generated by different versions of Cas9.
The successful implementation of the above outlined research proposal will constitute a significant contribution to the field of DNA repair and the diseases caused by defects in these pathways.
Joanna Loizou joined CeMM in 2011. She completed her undergraduate studies in the UK, moving there from Cyprus. Subsequently, she commenced PhD work at the University of Manchester UK, investigating mechanisms of DNA repair. Postdoctoral work followed at the International Agency for Research on Cancer (IARC), WHO, France where Joanna investigated the regulation and importance of epigenetic modifications in DNA repair. During this time, she chose to work on the immune system and demonstrated that histone acetylation is important in maintaining hematopoietic stem cells. Building on this experience she focused on the role of genomic instability in cancers of the blood and at the London Research Institute (LRI), Cancer Research UK (CR-UK), she investigated DNA repair in the development of the immune system and in suppressing lymphoma. At CeMM, Joanna’s group investigates the mechanisms by which cells respond to – and repair – DNA damage to maintain genomic stability and suppress tumorigenesis and other rare hereditary diseases.
Owusu M, et al. Mapping the human kinome in response to DNA damage. Cell Rep. 2019; Jan 15;26(3):555-563.e6. (abstract)
Map of synthetic rescue interactions for the Fanconi anemia DNA repair pathway identifies USP48. Velimezi G, Robinson-Garcia L, Muñoz-Martínez F, Wiegant WW, Ferreira da Silva J, Owusu M, Moder M, Wiedner M, Rosenthal SB, Fisch KM, Moffat J, Menche J, van Attikum H, Jackson SP, Loizou JI. Nature Communications, Jun 11;9(1):2280, 2018 (abstract)
Zou X, Owusu M, et al. Validating the concept of mutational signatures with isogenic cell models. Nat Commun. 2018 May 1;9(1):1744. (abstract)
Repair of UV-Induced DNA Damage Independent of Nucleotide Excision Repair Is Masked by MUTYH. Mazouzi A, Battistini F, Moser SC, Ferreira da Silva, Wiedner M, Owusu M, Lardeau C-H, Ringler A, Weil B, Neesen J, Orozco M, Kubicek S, Loizou JI. Molecular Cell Nov 16;68(4):797-807, 2017 (abstract)
Parallel genome-wide screens identify a synthetic viable interaction between the BLM helicase complex and Fanconi anemia. Moder M, Velimezi G, Owusu M, Mazouzi A, Wiedner M, Ferreira da Silva J, Robinson-Garcia L, Schischlik F, Slavkovsky R, Kralovics R, Schuster M, Bock C, Ideker T, Jackson SP, Menche J, Loizou JI. Nature Communications Nov 1;8(1):1238, 2017 (abstract)
ATMIN is required for maintenance of genomic stability and suppression of B cell lymphoma. Loizou JI, Sancho R, Kanu N, Bolland B, Yang F, Rada C, Corcoran AE, Behrens A. Cancer Cell 19:587-600, 2011 (abstract)
Histone acetylation by Trrap/Tip60 HAT modulates loading of repair proteins to DNA breaks and repair of DNA double strand breaks. Murr R*, Loizou JI*, Yang Y-G, Cuenin C, Li H, Wang Z-Q, Herceg Z. Nature Cell Biology 8:91-99, 2006 *equal contribution (abstract)
The protein kinase CK2 facilitates repair of chromosomal DNA single-strand breaks. Loizou JI, El-Khamisy SF, Zlatanou A, Moore DJ, Chan DW, Qin J, Sarno, S, Meggion F, Pinna LA, Caldecott KW. Cell 117:17-28, 2004 (abstract)