Dr. Ron Jachimowicz
Research Area: DNA Repair and Genome Integrity
Branches: Cancer BiologyGenetics
1. Research Background:
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 ensures that the consequences of DNA damage are held to a minimum. Consequently, defects inDNA repair pathways 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, increased cancer susceptibility, neurodegeneration and immunodeficiency. The identification of Ataxia- telangiectasia or Rothmund Thompson syndrome, for example, contributed significantly to our mechanistic understanding of the DNA damage response and ageing-related pathways. A closer investigation of patients with human genome instability syndromes thus provides a rich and unparalleled opportunity to uncover novel pathways in a meaningful organism (Jachimowicz et al., Cell Cycle, 2019).
In this way we have recently identified a deleterious UBQLN4 mutation in families with an autosomal recessive genome instability syndrome, termed UBQLN4 deficiency syndrome (Jachimowicz et al., Cell, 2019). UBQLN4 belongs to the family of Ubiquilins and most studies of mammalian Ubiquilins have focused on their roles in protein degradation, describing them as adaptors in delivering substrates to the proteasome. We identified that UBQLN4 interacts with MRE11 to repress early steps of homologous recombinationrepair (HRR). RNA-sequencing data together with clinical data of cancer patients revealed that UBQLN4 expression levels are frequently elevated in numerous cancers. Moreover, elevated UBQLN4 expression correlates with poor overall survival in these cancers. The importance of UBQLN4 for DNA repair is highlighted by the switch-like role UBQLN4 assumes in the DNA double-strand repair (DSB) pathway choice: loss of UBQLN4, as observed in the identified UBQLN4 deficiency syndrome, promotes HRR, whereas overexpression of UBQLN4, as observed in aggressive cancers, represses HRR in favor of non-homologous end-joining (NHEJ). In line with an HRR defect in these aggressive tumors, UBQLN4 overexpression is associated with PARP1 inhibitor sensitivity in vitro and thus may offer a therapeutic window for PARP1 inhibitor treatment in UBQLN4 overexpressing tumors.
2. Research questions addressed by the group:
Our overarching research framework aims to provide a better understanding of the relationship between genome maintenance, ageing and cancer in an interdisciplinary approach. In order to achieve this goal, we identify novel genome instability syndromes, just as the above mentioned UBQLN4 deficiency syndrome. We further place emphasis on the DSB repair pathway choice of HRR vs. NHEJ due to its highly relevant translation of treatment rationale in cancer patients. UBQLN4 overexpression for instance represses HRR and favors NHEJ, thus potentially creating a druggable window for UBQLN4 overexpressing cancers with PARP1 inhibitors.
Thus, the overall research concept therefore follows a three-pronged approach:
- To identify and functionally characterize DNA repair defects and pathways in novel human genome instability syndromes.
- To identify and mechanistically dissect signaling pathways that are connected to DSB repair pathway choice.
- To assess the role of Ubqln4 gain and loss of function in mouse models of cancer.
3. Applied Methods and model organisms:
We dissect defects in DNA repair pathways in patients with genome instability syndromes, involving tools from 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 ageing associated diseases. Specifically, we apply the following methods:
- patient screening (clinical and next-generation sequencing data)
- Retro- and lentivirus generation
- high-throughput immunofluorescence screens
- high-throughput viability and drug combinatorial screens
- CRISPR/Cas9 screens
- DNA repair fluorescent reporter assays
- further DNA repair assays (Comet assay, SMART, DNA damage recruitment)
- mouse modeling, phenotyping, imaging and treatment of tumors and model organisms:
- humans (patients, patient-derived fibroblasts, human cell lines)
- mouse models to mimic novel genome instability syndromes and mouse models of cancer
4 Desirable skills and qualifications:
We seek a highly motivated and creative candidate to join an enthusiastic and collaborative team in a vibrant scientific environment.Candidates with strong laboratory and analytical skills and a background in molecular biology, biochemistry, computational biology or in vivo mouse models are highly encouraged to apply.
- Jachimowicz, R. D., Goergens, J. & Reinhardt, H. C. DNA double-strand break repair pathway choice -from basic biology to clinical exploitation. Cell Cycle, 1-12, doi:10.1080/15384101. 2019.1618542 (2019).
- Jachimowicz, R. D. et al. UBQLN4 Represses Homologous Recombination and Is Overexpressed in Aggressive Tumors. Cell 176, 505-519 e522, doi:10.1016/j.cell.2018.11.024 (2019).