The tousled-like kinases and their implications in cancer and neurodevelopmental disorders
- Autores: Marina Villamor Paya
- Directores de la Tesis: Travis Stracker (dir. tes.), Albert Tauler Girona (tut. tes.)
- Lectura: En la Universitat de Barcelona ( España ) en 2021
- Idioma: inglés
- Tribunal Calificador de la Tesis: Neus Agell Jané (presid.), Susana de la Luna Gargantilla (secret.), Guillermo de Cárcer Díez (voc.)
- Programa de doctorado: Programa de Doctorado en Biomedicina por la Universidad de Barcelona
- Materias:
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- Resumen
The Tousled like kinases 1 and 2 (TLK1 and TLK2) are evolutionarily conserved Ser/Thr kinases that are required for genome stability and normal development in numerous organisms. Both kinases contribute to histone deposition by targeting the histone chaperone ASF1 and are regulated by the DNA damage response. Their expression is ubiquitous and often elevated in cancer cells with suppressed immune gene expression. In cultured cells, TLK depletion causes replication stress, DNA damage and altered chromatin maintenance, eliciting an innate immune response dependent on the Alternative-lengthening of telomeres pathway. This suggested that TLKs would be a potential target in cancer therapy. In addition, TLKs have been linked to a distinct neurodevelopmental disorder (NDD) known as Mental Retardation Autosomal Dominant (MRD57). How TLKs contribute to these pathologies remains largely unknown. The aims of this thesis are to explore the therapeutic potential of targeting TLKs in cancer and understand how TLK2 deficiency contributes to NDDs. To this end, we have generated conditional mouse models where we can modulate TLK2 expression in both embryonic development and in developing breast cancer. We have also mimicked TLK2 mutations from MRD57 patients in vitro and addressed how they alter the normal kinase activity, localization and interactome of TLK2. We showed that depletion of TLK2 in already formed tumors stalls tumor growth and reduces lung metastases, and observed an early immune infiltration that could potentially sensitize these tumors to immune checkpoint blockade. Novel small molecule inhibitors towards TLKs were identified, indicating that they are inherently druggable targets.
Consistent with what we observed in cancer, deletion of TLK2 in the telencephalon of mouse embryos caused elevated transcription of inflammatory genes and signatures of microglia and astrocytes. We also described 6 new cases of MRD57 and showed that patient-derived cell lines exhibited defects in chromatin compaction. Separately we identified two hyperactive MRD57 mutations, suggesting misregulation of TLK2 levels, rather than decreased activity, is likely the predisposing factor leading to NDD. Lastly, we showed in cells that TLK2 is in close proximity with a number of known autism-susceptibility proteins and proteins enriched in replication forks, and that these proximal interactions are altered by MRD57 mutations. Together, these results further suggest that TLKs may be a viable target for cancer therapy, as their loss leads to innate immune activation that may also influence neurodevelopment in MRD57 patients.
