Detail

Keywords

CRISPR-Cas Systems; DNA Breaks; DNA Repair

Research interests

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. Our three main focus areas are:

1. Consequences of DNA damage and repair on genomic mutation signatures
2. Synthetic lethal and viable interactions
3. Repair of CRISPR-Cas9 generated DNA breaks

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.

Techniques, methods & infrastructure

My team investigates the cellular pathways that respond to DNA damage, to maintain genome stability and suppress cancer development. Our goal is to piece together the intricate puzzle that encompasses the human DNA damage response at the cellular level, hence providing a complete understanding of how such pathways go wrong in disease states, with a strong emphasis on cancer. To achieve this, we use global approaches, based around genetics, genomics, proteomics and chemical biology.

Grants

• Crosstalk between cellular metabolism and DNA repair (2019)
  Source of Funding: FWF (Austrian Science Fund), Stand Alone
  Principal Investigator
• DDREAMM: Dna Damage REsponse: Actionabilities, Maps and Mechanisms (2019)
  Source of Funding: EU, ERC Synergy
  Principal Investigator
• Targeted protein degredation: From small molecules to complex organelles (2019)
  Source of Funding: FWF (Austrian Science Fund), SFB
  Principal Investigator

Selected publications

1. Owusu, M. et al., 2019. Mapping the Human Kinome in Response to DNA Damage. Cell Reports, 26(3), pp.555–563.e6. Available at: http://dx.doi.org/10.1016/j.celrep.2018.12.087.
2. Velimezi, G. et al., 2018. Map of synthetic rescue interactions for the Fanconi anemia DNA repair pathway identifies USP48. Nature Communications, 9(1). Available at: http://dx.doi.org/10.1038/s41467-018-04649-z.
3. Zou, X. et al., 2018. Validating the concept of mutational signatures with isogenic cell models. Nature Communications, 9(1). Available at: http://dx.doi.org/10.1038/s41467-018-04052-8.
4. Mazouzi, A. et al., 2017. Repair of UV-Induced DNA Damage Independent of Nucleotide Excision Repair Is Masked by MUTYH. Molecular Cell, 68(4), pp.797–807.e7. Available at: http://dx.doi.org/10.1016/j.molcel.2017.10.021.
5. Moder, M. et al., 2017. Parallel genome-wide screens identify synthetic viable interactions between the BLM helicase complex and Fanconi anemia. Nature Communications, 8(1). Available at: http://dx.doi.org/10.1038/s41467-017-01439-x.