TY - JOUR
T1 - Acute expression of human APOBEC3B in mice results in RNA editing and lethality
AU - Alonso de la Vega, Alicia
AU - Temiz, Nuri Alpay
AU - Tasakis, Rafail
AU - Somogyi, Kalman
AU - Salgueiro, Lorena
AU - Zimmer, Eleni
AU - Ramos, Maria
AU - Diaz-Jimenez, Alberto
AU - Chocarro, Sara
AU - Fernández-Vaquero, Mirian
AU - Stefanovska, Bojana
AU - Reuveni, Eli
AU - Ben-David, Uri
AU - Stenzinger, Albrecht
AU - Poth, Tanja
AU - Heikenwälder, Mathias
AU - Papavasiliou, Nina
AU - Harris, Reuben S.
AU - Sotillo, Rocio
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - Background: RNA editing has been described as promoting genetic heterogeneity, leading to the development of multiple disorders, including cancer. The cytosine deaminase APOBEC3B is implicated in tumor evolution through DNA mutation, but whether it also functions as an RNA editing enzyme has not been studied. Results: Here, we engineer a novel doxycycline-inducible mouse model of human APOBEC3B-overexpression to understand the impact of this enzyme in tissue homeostasis and address a potential role in C-to-U RNA editing. Elevated and sustained levels of APOBEC3B lead to rapid alteration of cellular fitness, major organ dysfunction, and ultimately lethality in mice. Importantly, RNA-sequencing of mouse tissues expressing high levels of APOBEC3B identifies frequent UCC-to-UUC RNA editing events that are not evident in the corresponding genomic DNA. Conclusions: This work identifies, for the first time, a new deaminase-dependent function for APOBEC3B in RNA editing and presents a preclinical tool to help understand the emerging role of APOBEC3B as a driver of carcinogenesis.
AB - Background: RNA editing has been described as promoting genetic heterogeneity, leading to the development of multiple disorders, including cancer. The cytosine deaminase APOBEC3B is implicated in tumor evolution through DNA mutation, but whether it also functions as an RNA editing enzyme has not been studied. Results: Here, we engineer a novel doxycycline-inducible mouse model of human APOBEC3B-overexpression to understand the impact of this enzyme in tissue homeostasis and address a potential role in C-to-U RNA editing. Elevated and sustained levels of APOBEC3B lead to rapid alteration of cellular fitness, major organ dysfunction, and ultimately lethality in mice. Importantly, RNA-sequencing of mouse tissues expressing high levels of APOBEC3B identifies frequent UCC-to-UUC RNA editing events that are not evident in the corresponding genomic DNA. Conclusions: This work identifies, for the first time, a new deaminase-dependent function for APOBEC3B in RNA editing and presents a preclinical tool to help understand the emerging role of APOBEC3B as a driver of carcinogenesis.
KW - APOBEC3B
KW - DNA damage
KW - Mouse models
KW - Mutations
KW - RNA editing
UR - http://www.scopus.com/inward/record.url?scp=85177771194&partnerID=8YFLogxK
U2 - 10.1186/s13059-023-03115-4
DO - 10.1186/s13059-023-03115-4
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C2 - 38001542
AN - SCOPUS:85177771194
SN - 1474-7596
VL - 24
JO - Genome Biology
JF - Genome Biology
IS - 1
M1 - 267
ER -
