Completed Projects · Oncology

Team DDC

DNA Damage in Cancer

Often termed as a disease of the genome, cancer is the result of random acquisition of mutations that activate oncogenes and inactivate tumor suppressors. Consequently, cellular processes including cell cycle control, transcription, apoptosis and DNA repair are affected, conferring incremental growth advantages to cells and fomenting tumorigenesis. Advances in next-generation DNA sequencing have recently enabled the detailed characterization of molecular processes leading to such DNA alterations in cancer. It became immediately clear that alterations in DNA repair pathways could predispose cells to accumulating DNA damage. On the other hand, several drugs used in cancer treatment indeed target DNA repair pathways. Although this seems like a paradox in cancer treatment, it also spawns new avenues for therapeutical options through the use of synthetic lethality in cancer cells.

Our group is interested in extending the list of drugs that take advantage of the crosstalk between DNA repair genes and developing educated designs of targeted therapies for individual tumor types. We combine cancer genomics, genetic screening approaches and pre-clinical studies in order to dissect synthetic lethality mechanisms of DNA repair in human cells that can also act together with radio or chemotherapy. To this end, we perform detailed genetic and molecular characterization of DNA repair proteins based on tumor-specific somatic or germline alterations in cancer and apply CRISPR-Cas9 based genetic screens. Together, our research aims to understand the sensitivity or resistance of tumors to various treatment regimens and how inducing defects in DNA repair machinery can be used to selectively target tumors.

Publications

  1. Serçin Ö, Reither S, Roidos P, Ballin N, Palikyras S, Baginska A, Rein K, Llamazares M, Halavatyi A, Winter H, Muley T, Jurkowska RZ, Abdollahi A, Zenke FT, Neumann B, Mardin BR (2019):
    A solid-phase transfection platform for arrayed CRISPR screens
    Molecular Systems Biology 15 (12)
  2. Drainas AP, Lambuta RA, Ivanova I, Serçin Ö, Sarropoulos I, Smith ML, Efthymiopoulos T, Raeder B, Stütz AM, Waszak SM, Mardin BR, Korbel JO (2020):
    Genome-wide Screens Implicate Loss of Cullin Ring Ligase 3 in Persistent Proliferation and Genome Instability in TP53-Deficient Cells
    Cell Reports 31(1)
  3. Roidos P, Sungalee S, Benfatto S, Serçin Ö, Stütz AM, Abdollahi A, Mauer J, Zenke FT, Korbel JO, Mardin BR (2020):
    A scalable CRISPR/CAS9-based fluorescent reporter assay to study DNA double-strand break repair choice
    Nature Communications 11, 4077 (2020)
  4. Dejure F, Butzer J, Lindemann RK, Mardin BR (2020):
    Exploiting the metabolic dependencies of the broad amino acid transporter SLC6A14
    Oncotarget. 2020; 11: 4490-4503
  5. Benfatto S, Serçin Ö, Dejure FR, Abdollahi A, Zenke FT, Mardin BR (2021):
    Uncovering cancer vulnerabilities by machine learning prediction of synthetic lethality
    Molecular Cancer. 2021; 20:111

The research of this team was kindly sponsored by Merck.

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