Die Rolle des Stress-induzierten Transkriptionsfaktors X-box binding protein 1 in der Koordination DNA-Schaden-abhängiger intestinaler Entzündung und Tumorigenese

The inflammatory bowel disease (IBD) risk gene X-box protein 1 essentially coordinates epithelial cell function and contributes to intestinal mucosal homeostasis. The gut of IBD patients is subjected to chronic inflamamtion which heighten the probability for epithelial damage, especially DNA damage. Ribonuclease H2 facilitates ribonucleotide excision repair and loss of epithelial ribonuclease H2 subunit B (RNASEH2B) leads to the development of DNA damage.

The aim of this thesis was to evaluate whether X-box protein 1 is involved in intestinal epithelial DNA damage responses during inflammation. 

Simultaneous deficiency of epithelial X-box protein 1 (Xbp1) and Rnaseh2b leads to impaired epithelial regeneration in-vitro and in-vivo, causing the generation of aggressive metastatic intestinal adenocarcinoma in mice. Mechanistically, Xbp1 restrains intestinal stem cell proliferation and consecutive carcinogenesis via p53-DNA damage inducible transcript 4-like–mediated mechanistic target of rapamycin inhibition.