Research Group Leader - MPI for Biology of Ageing
Dr. Ron D. Jachimowicz
Mechanisms of DNA Repair Laboratory
MPI for Biology of Ageing
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:
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.
Figure 1: Role of UBQLN4 in DNA repair and disease.