Mechanisms of DNA Repair
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 UBQLN4deficiency 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.
Utilizing patients with mutations that affect genome maintenance as a model to study DNA repair mechanisms, we aim to understand:
How defective DNA repair rewires ageing- and cancer pathways
The occurrence of premature ageing and DNA repair defects in human genome instability syndromes creates a unique opportunity to identify and investigate novel components of DNA repair pathways. Furthering our understanding of the mechanisms underlying novel genome instability syndromes allows us to examine their crucial role in ageing, ageing-associated diseases, and cancer.
How UBQLN4 overexpression may be utilized for targeted cancer treatment
It is conceivable that UBQLN4 overexpression is selected in cancer cells, since it facilitates effective coping with endogenous DSBs, including those occurring during replicative stress. While this largely NHEJ-mediated, more effective DSB sealing in UBQLN4 overexpressing cells protects them from acute genotoxic stress, it is likely to be highly mutagenic, as NHEJ is an error-prone mechanism. Thus, NHEJ-driven mutagenesis may also be selected for in cancer cells, since it further promotes genome instability and oncogenic transformation. We study the effect of UBQLN4 overexpression in vivo utilizing genetically engineered mouse models and focus on the possibility of DNA repair defective targeting to precipitate novel treatment strategies.
How DNA repair defects expose genotype-specific vulnerabilities in mantle cell lymphoma
Somatic mutations in ATM are observed in approximately 50% of mantle cell lymphoma cases, but no targeted treatment options exist to date for this major genetic subtype. Innovative treatments are hence urgently needed, especially for the growing population of older mantle cell lymphoma patients who are not eligible for intensified therapies. Functionally, ATM plays a critical role for DSB repair, and there is strong evidence for ATM in HRR-mediated DSB repair. However, a chemotherapy-resistance is observed in ATM-deficient cancers which indicates that DSBs are repaired in ATM-deficient tumors. It is likely that alternative, error-prone DSB repair pathways, such as NHEJ compensate for the HRR defect in ATM-deficient tumors. Thus, by identifying backup DNA repair pathways in ATM-defective mantle cell lymphoma we aim to identify targeted treatment options for these patients.
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 this research program thus contribute to a deepened functional understanding of genome maintenance and DNA repair in the context of ageing and cancer.