CECAD

Dr. Ron D. Jachimowicz

Research Group Leader - MPI for Biology of Ageing

 

Dr. Ron D. Jachimowicz
Principal Investigator CECAD Cologne
 +49 - (0)221 - 37 970 - 580
ron.jachimowicz[at]age.mpg.de

Mechanisms of DNA Repair Laboratory
MPI for Biology of Ageing
Joseph-Stelzmann-Str. 9b

50931 Köln

Foto: Michael Wodak / MFK

The integrity of our genome needs to be preserved to ensure the faithful passage of genetic information to our progeny. An extensive network of DNA repair pathways ensure that the consequences of DNA damage are held to a minimum. Defects in DNA repair pathways thus promote genome instability and are a central contributor to ageing and carcinogenesis.

Supporting the importance of genome stability on an organismal level, human genome instability syndromes frequently share clinical features of premature ageing and ageing-associated diseases, including increased cancer susceptibility, neurodegeneration, and immunodeficiency. For example, the identification of Ataxia-telangiectasia—the disease underlying germline ATM mutations— contributed significantly to our mechanistic understanding of the DNA damage response, as well cancer- and ageing-related pathways. Somatic mutations in ATM are further commonly found in mantle cell lymphoma, a mature B-cell lymphoma typically affecting the elderly, for which mechanism-based therapies are scarce with poor overall treatment outcome.

Our research: Our research aims to provide a better understanding of the relationship between genome maintenance, ageing, and cancer, in an interdisciplinary approach. We dissect defects in DNA repair pathways in patients with genome instability syndromes and in patients suffering from mantle cell lymphoma, providing a rich and unparalleled opportunity to uncover novel pathways in a meaningful organism.

Utilizing patients with alterations that affect genome maintenance as a model to study DNA repair mechanisms, we aim to understand:

  1. How defective DNA repair rewires ageing- and cancer pathways
  2. How UBQLN4 overexpression may be utilized for targeted cancer treatment
  3. How DNA repair defects expose genotype-specific vulnerabilities in mantle cell lymphoma

Our goals: The overarching goal of our research program is to understand disease mechanisms in patients with an underlying genome instability syndrome and DNA repair deficient mantle cell lymphoma. We strive to identify novel therapeutic approaches based on DNA repair. Associated molecular liabilities discovered in our research program will contribute to a deepened functional understanding of genome maintenance and DNA repair in the context of ageing and cancer.

Our successes: In one stream of research, we recently identified a deleterious UBQLN4 mutation in families with an autosomal recessive syndrome reminiscent of genome instability disorders, which we termed UBQLN4 deficiency syndrome. Affected patients display mild clinical signs of premature ageing and typical features of genome instability. Crucially, we found that UBQLN4 interacts with ubiquitylated MRE11 to mediate early steps of homologous recombination repair (HRR). HRR depends on a 5’-3’ double-strand break (DSB) end resection, which is initiated by the MRE11 nuclease. Loss of UBQLN4, as we identified in this novel genome instability syndrome, leads to chromatin retention of MRE11, promoting non-physiological HRR activity both in vitro and in vivo. Scrutinizing RNA-sequencing data together with clinical data of cancer patients, we observed that UBQLN4 expression levels are frequently elevated in numerous aggressive cancers. The importance of UBQLN4 for DNA repair is highlighted by the switch-like role UBQLN4 assumes in the DSB repair pathway choice: loss of UBQLN4, as observed in the UBQLN4 deficiency syndrome, promotes HRR, whereas overexpression of UBQLN4, as observed in aggressive cancers, represses HRR in lieu of non-homologous end-joining (NHEJ). In line with an HRR defect in these aggressive tumors, we found that UBQLN4 overexpression is associated with PARP1 inhibitor sensitivity in vitro and may thus offer a therapeutic window for PARP1 inhibitor treatment in UBQLN4 overexpressing tumors.

Our methods/techniques: We utilize tools involving biochemistry, cell biology, computational biology, and transfer these findings to modern mouse genetics, that will ultimately lead to genetically-informed therapies for patients suffering from cancer and ageing associated diseases.

Figures

Figure 1: Role of UBQLN4 in DNA repair and disease.

EXTERNAL Cooperations
  • Dr. Filippo Beleggia, University of Cologne
  • Prof. Dr. Arndt Borkhardt, Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Heinrich Heine University Düsseldorf
  • Prof. Dr. Reinhard Büttner, Department of Pathology, University Hospital Cologne
  • Prof. Dr. Felix Distelmaier, Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Hospital, Heinrich-Heine-University Düsseldorf
  • Prof. Dr. Matthias Fischer, Department of Experimental Pediatric Oncology, University Hospital Cologne
  • Prof. Dr. Dave SB Hoon, Department of Translational Molecular Medicine, John Wayne Cancer Institute, CA, USA
  • Prof. Dr. Tim Hucho, Department of Anesthesiology and Intensive Care Medicine, Experimental Anesthesiology and Pain Research, University Hospital Cologne
  • Prof. Dr. Pablo Huertas, Centro Andaluz de Biologıa Molecular y Medicina Regenerativa-CABIMER, University of Sevilla
  • Prof. Dr. Wolfram Klapper, University Hospital Schleswig-Holstein, Christian-Albrechts-University Kiel
  • Prof. Dr. Davut Pehlivan, Department of Molecular and Human Genetics, Baylor College of Medicine, TX, USA
  • Prof. Dr. Martin Peifer, Center for Molecular Medicine Cologne, University of Cologne
  • Prof. Dr. Christian Reinhardt, Westdeutsches Tumorzentrum Essen, University Hospital Essen
  • Prof. Dr. Yosef Shiloh, The David and Inez Myers Laboratory for Cancer Genetics, Sackler School of Medicine, Tel Aviv University
  • Prof. Dr. Roman Thomas, Department of Translational Genomics, University of Cologne
  • Prof. Dr. Dagmar Wieczorek, Institute of Human Genetics, Heinrich-Heine-University Düsseldorf
  • Prof. Dr. Bernd Wollnik, Institute of Human Genetics, University Medical Center Göttingen
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