eprintid: 33032
rev_number: 14
eprint_status: archive
userid: 7280
dir: disk0/00/03/30/32
datestamp: 2023-03-24 09:42:58
lastmod: 2023-12-11 10:10:10
status_changed: 2023-03-24 09:42:58
type: doctoralThesis
succeeds: 33030
metadata_visibility: show
creators_name: Alonso de la Vega, Alicia
title: Uncovering the role of APOBEC3B in lung cancer and RNA editing
subjects: ddc-570
divisions: i-140001
adv_faculty: af-14
cterms_swd: Cancer
cterms_swd: Mutations
cterms_swd: APOBEC3B
abstract: De novo genetic alterations such as DNA mutations, chromosomal instability and other mechanisms like RNA editing, can all induce tumor heterogeneity. Members of the APOBEC3 family of cytosine deaminases have been implicated in increased cancer genome mutagenesis, thereby contributing to intra- and inter tumor genomic heterogeneity and therapy resistance. Among the APOBEC3 family, APOBEC3A (A3A) and APOBEC3B (A3B) have been causally linked to the observed APOBEC mutation signature in several cancers. It is essential to understand how these conserved enzymes with a key role in innate defense can turn against the host endangering the genome. Recent studies on A3B, have generated new insights into how A3B mutagenesis and chromosomal instability fuels tumor evolution. However, there is still a long way to go in understanding the actual impact of A3B expression in cancer and its implication in other possible mechanisms driving diversity, such as RNA editing.
To better understand the impact of A3B in tissue homeostasis and tumor evolution, we engineered a novel doxycycline-inducible mouse model of A3B-overexpression. The data in this thesis uncovered that A3B can influence tumorigenesis at different stages. First, long-term A3B expression fueled tumor initiation in different tissues. In addition, A3B expression combined with a well-described model of Kras-driven lung adenocarcinoma promoted malignant progression. Although overexpression of A3B did not affect overall survival, tumors acquired advanced disease features similar to those seen in human lung malignancies. The aggressiveness of A3B expression was also reflected in partial tumor regression upon direct oncogene inhibition. Finally, A3B tumor cells downregulate the p53 pathway as a bypass mechanism to tolerate A3B-induced damage. In summary, the first part of this thesis unveils that A3B expression enables tumor cells to evolve and acquire traits to drive tumor evolution.
To study a potential role of A3B as and RNA editing enzyme I engineered a mouse model that achieves strong and persistent levels of A3B in healthy tissues, leading to disruption of cellular fitness and causing sudden animals’ death. Liver and pancreas were the main organs affected, correlating with being the tissues with higher A3B expression. Importantly, strict analysis of whole exome and transcriptomic data from A3B tissues revealed hundreds of A3B- driven RNA editing events localized in a particular sequence context: UCCGUGUG. In addition, the labile nature of RNA editing was confirmed by undetectable editing activity in the absence of A3B expression. Finally, I discovered that RNA editing activity is dependent on the deaminase catalytic domain of A3B. This work illustrates how elevated levels of A3B are toxic and dramatically compromise cell and tissue homeostasis and identifies, for the first time, a new function of A3B in editing the RNA.
date: 2023
id_scheme: DOI
id_number: 10.11588/heidok.00033032
ppn_swb: 1873037953
own_urn: urn:nbn:de:bsz:16-heidok-330320
date_accepted: 2022-12-09
advisor: HASH(0x559e37f42960)
language: eng
bibsort: ALONSODELAUNCOVERING
full_text_status: public
place_of_pub: Heidelberg
citation:   Alonso de la Vega, Alicia  (2023) Uncovering the role of APOBEC3B in lung cancer and RNA editing.  [Dissertation]     
document_url: https://archiv.ub.uni-heidelberg.de/volltextserver/33032/7/Final-AADV-uni.pdf