Principal Investigator
We dissect defects in DNA repair pathways in patients with genome instability syndromes and in patients suffering from mantle cell lymphoma, providing a rich opportunity to uncover the relationship between genome maintenance, aging, and cancer.
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 aging and cancer.
We dissect defects in DNA repair pathways in novel human genome instability syndromes and in patients suffering from mantle cell lymphoma, providing a rich and unparalleled opportunity to uncover rewired DNA signaling.
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 aging and typical features of genome instability. Crucially, we found that UBQLN4 interacts with ubiquitylated MRE11 to mediate early steps of homologous recombination repair (HR). HR 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 HR 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 HR, whereas overexpression of UBQLN4, as observed in aggressive cancers, represses HR in lieu of non-homologous end-joining (NHEJ). In line with an HR 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.
Principal Investigator