Universität zu Köln

Tobergte (geb. Hützen), Maxim Alexander ORCID: 0009-0008-2217-813X (2026). From Rare Syndromes to DNA Repair Mechanisms: UBQLN1 Regulates Homologous Recombination and Exposes Actionable Cancer Vulnerabilities. PhD thesis, Universität zu Köln.

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Abstract

Genomic integrity is continuously challenged by DNA damage. Cells have evolved complex repair mechanisms to maintain tissue homeostasis. The study of rare genome instability syndromes caused by defects in these repair pathways can reveal previously unrecognized DNA repair factors and regulatory mechanisms. Many of these syndromes are associated with cancer predisposition, highlighting the direct link between impaired DNA repair and tumorigenesis. Understanding the mechanisms underlying these syndromes may therefore reveal exploitable tumor-specific dependencies, with implications beyond rare syndromes. This dissertation spans syndrome characterization, mechanistic investigation, and preclinical therapeutic studies. The four integrated manuscripts illustrate this trajectory. Biallelic variants in Cysteine-Rich Interactor of PDZ Three (CRIPT) cause a progeroid disorder driven by cellular senescence without detectable DNA damage sensitivity, demonstrating how functional studies distinguish phenotypically overlapping conditions from DNA repair deficiencies. Optical genome mapping in a pediatric cohort with suspected cancer predisposition improves diagnostic capacity for structural variant detection. A de novo duplication encompassing Replication Protein A1 (RPA1) identified in this cohort is associated with genotoxic hypersensitivity. The central study, discovery and characterization of the Ubiquilin-1 (UBQLN1) deficiency syndrome, reveals that UBQLN1 regulates homologous recombination (HR) repair by shielding the recombinase RAD51 from ubiquitin-dependent proteasomal degradation. Loss of UBQLN1 destabilizes RAD51 and impairs accurate DNA repair via HR. By contrast, UBQLN1 overexpression promotes degradation of the DNA repair nuclease MRE11 and is associated with excessive DNA end resection and engagement of alternative mutagenic repair pathways. UBQLN1 is frequently overexpressed in aggressive human cancers. In a KrasG12D-driven lung cancer mouse model, Ubqln1 overexpression emerges as a candidate biomarker for tumor aggressiveness and for sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition and immune checkpoint blockade, with the potential to improve therapeutic stratification in the clinic. Lastly, in a target-directed approach, development of Deltafluorine, a first-in-class covalent phosphodiesterase δ (PDEδ) inhibitor, enables targeting of oncogenic KRAS membrane trafficking. Treatment of the KrasG12D-driven mouse model with Deltafluorine reduces tumor burden in vivo. Overall, this work demonstrates how investigating rare syndromes alongside target-directed therapeutic development can identify mechanisms and vulnerabilities relevant to cancer therapy.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Tobergte (geb. Hützen), Maxim Alexander mhuetzen@age.mpg.de https://orcid.org/0009-0008-2217-813X UNSPECIFIED
URN:	urn:nbn:de:hbz:38-809949
Date:	2026
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Außeruniversitäre Forschungseinrichtungen > MPI for Biology of Ageing
Subjects:	Generalities, Science Natural sciences and mathematics Chemistry and allied sciences Life sciences Technology (Applied sciences) Medical sciences Medicine
Uncontrolled Keywords:	Keywords Language Genome instability syndrome English DNA repair English Ubiquilin English Homologous recombination English CRIPT English UBQLN1 English Optical genome mapping English RAD51 English KRAS English Deltafluorine English KP mouse English
Date of oral exam:	12 June 2026
Referee:	Name Academic Title Gehring, Niels Professor Schermer, Bernhard Professor
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/80994