Acute expression of human APOBEC3B in mice results in RNA editing and lethality

Alicia Alonso de la Vega; Nuri Alpay Temiz; Rafail Tasakis; Kalman Somogyi; Lorena Salgueiro; Eleni Zimmer; Maria Ramos; Alberto Diaz-Jimenez; Sara Chocarro; Mirian Fernández-Vaquero; Bojana Stefanovska; Eli Reuveni; Uri Ben-David; Albrecht Stenzinger; Tanja Poth; Mathias Heikenwälder; Nina Papavasiliou; Reuben S. Harris; Rocio Sotillo

doi:10.1186/s13059-023-03115-4

Acute expression of human APOBEC3B in mice results in RNA editing and lethality

Alicia Alonso de la Vega
, Nuri Alpay Temiz
, Rafail Tasakis
, Kalman Somogyi
, Lorena Salgueiro
, Eleni Zimmer
, Maria Ramos
, Alberto Diaz-Jimenez
, Sara Chocarro
, Mirian Fernández-Vaquero
, Bojana Stefanovska
, Eli Reuveni
, Uri Ben-David
, Albrecht Stenzinger
, Tanja Poth
, Mathias Heikenwälder
, Nina Papavasiliou
, Reuben S. Harris
, Rocio Sotillo

German Cancer Research Center
Heidelberg University
University of Minnesota Twin Cities
University of Texas Health Science Center at San Antonio
Tel Aviv University
German Center for Lung Research (DZL)

Research output: Contribution to journal › Article › peer-review

14 Scopus citations

Abstract

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.

Original language	English
Article number	267
Journal	Genome Biology
Volume	24
Issue number	1
DOIs	https://doi.org/10.1186/s13059-023-03115-4
State	Published - 24 Nov 2023
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2023, The Author(s).

Funding

Open Access funding enabled and organized by Projekt DEAL. This work was in part supported by the Deutsches Zentrum für Lungenforschung (DZL, # 82DZL004A4) to R.S and a grant to RSH from the National Cancer Institute (P01-CA234228). RSH is the Margaret Harvey Schering Land Grant Chair for Cancer Research, a Distinguished University McKnight Professor, and an Investigator of the Howard Hughes Medical Institute.

Funders	Funder number
National Cancer Institute	P01-CA234228
Deutsches Zentrum für Lungenforschung	82DZL004A4

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

APOBEC3B
DNA damage
Mouse models
Mutations
RNA editing

Access to Document

10.1186/s13059-023-03115-4

Cite this

Alonso de la Vega, A., Temiz, N. A., Tasakis, R., Somogyi, K., Salgueiro, L., Zimmer, E., Ramos, M., Diaz-Jimenez, A., Chocarro, S., Fernández-Vaquero, M., Stefanovska, B., Reuveni, E., Ben-David, U., Stenzinger, A., Poth, T., Heikenwälder, M., Papavasiliou, N., Harris, R. S., & Sotillo, R. (2023). Acute expression of human APOBEC3B in mice results in RNA editing and lethality. Genome Biology, 24(1), Article 267. https://doi.org/10.1186/s13059-023-03115-4

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title = "Acute expression of human APOBEC3B in mice results in RNA editing and lethality",

abstract = "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.",

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month = nov,

day = "24",

doi = "10.1186/s13059-023-03115-4",

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Alonso de la Vega, A, Temiz, NA, Tasakis, R, Somogyi, K, Salgueiro, L, Zimmer, E, Ramos, M, Diaz-Jimenez, A, Chocarro, S, Fernández-Vaquero, M, Stefanovska, B, Reuveni, E, Ben-David, U, Stenzinger, A, Poth, T, Heikenwälder, M, Papavasiliou, N, Harris, RS & Sotillo, R 2023, 'Acute expression of human APOBEC3B in mice results in RNA editing and lethality', Genome Biology, vol. 24, no. 1, 267. https://doi.org/10.1186/s13059-023-03115-4

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

PY - 2023/11/24

Y1 - 2023/11/24

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 - https://www.scopus.com/pages/publications/85177771194

U2 - 10.1186/s13059-023-03115-4

DO - 10.1186/s13059-023-03115-4

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

C2 - 38001542

AN - SCOPUS:85177771194

SN - 1474-7596

VL - 24

JO - Genome Biology

JF - Genome Biology

IS - 1

M1 - 267

ER -

Acute expression of human APOBEC3B in mice results in RNA editing and lethality

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

Access to Document

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