APOBEC3G protects the genome of human cultured cells and mice from radiation-induced damage

Yelena Britan-Rosich; Jing Ma; Eran Kotler; Faizan Hassan; Alexander Botvinnik; Yoav Smith; Ofra Moshel; Abed Nasereddin; Gunjan Sharma; Eli Pikarsky; Susan Ross; Moshe Kotler

doi:10.1111/febs.16673

APOBEC3G protects the genome of human cultured cells and mice from radiation-induced damage

Yelena Britan-Rosich, Jing Ma, Eran Kotler, Faizan Hassan, Alexander Botvinnik, Yoav Smith, Ofra Moshel, Abed Nasereddin, Gunjan Sharma, Eli Pikarsky, Susan Ross^*, Moshe Kotler^*

^*Corresponding author for this work

Department of Immunology and Cancer Research

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

1 Scopus citations

Abstract

Cytosine deaminases AID/APOBEC proteins act as potent nucleic acid editors, playing important roles in innate and adaptive immunity. However, the mutagenic effects of some of these proteins compromise genomic integrity and may promote tumorigenesis. Here, we demonstrate that human APOBEC3G (A3G), in addition to its role in innate immunity, promotes repair of double-strand breaks (DSBs) in vitro and in vivo. Transgenic mice expressing A3G successfully survived lethal irradiation, whereas wild-type controls quickly succumbed to radiation syndrome. Mass spectrometric analyses identified the differential upregulation of a plethora of proteins involved in DSB repair pathways in A3G-expressing cells early following irradiation to facilitate repair. Importantly, we find that A3G not only accelerates DSB repair but also promotes deamination-dependent error-free rejoining. These findings have two implications: (a) strategies aimed at inhibiting A3G may improve the efficacy of genotoxic therapies used to cure malignant tumours; and (b) enhancing A3G activity may reduce acute radiation syndrome in individuals exposed to ionizing radiation.

Original language	American English
Pages (from-to)	1822-1839
Number of pages	18
Journal	FEBS Journal
Volume	290
Issue number	7
DOIs	https://doi.org/10.1111/febs.16673
State	Published - Apr 2023

Bibliographical note

Funding Information:
The authors thank David Ryan for assistance with the mouse breeding. We thank Dr Idit Shiff from the Core Research Facility of the Hebrew University‐Hadassah Medical School for the consultation and running the sequencing tasks. We thank Dr Jeremy Stark for providing the pimEJ5GFP (EJ5) plasmid and for his useful discussions. Authors are grateful to Prof Marc‐Andre Langlois, Faculty of Medicine, University of Ottawa, Canada for providing us the A3G RNA‐binding mutants. Funding information: This work was supported by the following grants: The National Institute for Allergy and Infectious Disease (R01AI085015 to SRR), by The Joint Israel‐Canada program (Grant No. 2665/16 MK), by The Milgrom Family Support Fund for projects in Military Medicine (4320614 MK) and partially by the Israel cancer association from the Abraham Rothstein fund (20200084 MK).

Funding Information:
The authors thank David Ryan for assistance with the mouse breeding. We thank Dr Idit Shiff from the Core Research Facility of the Hebrew University-Hadassah Medical School for the consultation and running the sequencing tasks. We thank Dr Jeremy Stark for providing the pimEJ5GFP (EJ5) plasmid and for his useful discussions. Authors are grateful to Prof Marc-Andre Langlois, Faculty of Medicine, University of Ottawa, Canada for providing us the A3G RNA-binding mutants. Funding information: This work was supported by the following grants: The National Institute for Allergy and Infectious Disease (R01AI085015 to SRR), by The Joint Israel-Canada program (Grant No. 2665/16 MK), by The Milgrom Family Support Fund for projects in Military Medicine (4320614 MK) and partially by the Israel cancer association from the Abraham Rothstein fund (20200084 MK).

Publisher Copyright:
© 2022 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

Keywords

APOBEC3G
DNA damage response
DNA repair
cytidine deaminase
homologous recombination
mouse
non-homologous end joining

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10.1111/febs.16673

Cite this

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title = "APOBEC3G protects the genome of human cultured cells and mice from radiation-induced damage",

abstract = "Cytosine deaminases AID/APOBEC proteins act as potent nucleic acid editors, playing important roles in innate and adaptive immunity. However, the mutagenic effects of some of these proteins compromise genomic integrity and may promote tumorigenesis. Here, we demonstrate that human APOBEC3G (A3G), in addition to its role in innate immunity, promotes repair of double-strand breaks (DSBs) in vitro and in vivo. Transgenic mice expressing A3G successfully survived lethal irradiation, whereas wild-type controls quickly succumbed to radiation syndrome. Mass spectrometric analyses identified the differential upregulation of a plethora of proteins involved in DSB repair pathways in A3G-expressing cells early following irradiation to facilitate repair. Importantly, we find that A3G not only accelerates DSB repair but also promotes deamination-dependent error-free rejoining. These findings have two implications: (a) strategies aimed at inhibiting A3G may improve the efficacy of genotoxic therapies used to cure malignant tumours; and (b) enhancing A3G activity may reduce acute radiation syndrome in individuals exposed to ionizing radiation.",

keywords = "APOBEC3G, DNA damage response, DNA repair, cytidine deaminase, homologous recombination, mouse, non-homologous end joining",

author = "Yelena Britan-Rosich and Jing Ma and Eran Kotler and Faizan Hassan and Alexander Botvinnik and Yoav Smith and Ofra Moshel and Abed Nasereddin and Gunjan Sharma and Eli Pikarsky and Susan Ross and Moshe Kotler",

note = "Funding Information: The authors thank David Ryan for assistance with the mouse breeding. We thank Dr Idit Shiff from the Core Research Facility of the Hebrew University‐Hadassah Medical School for the consultation and running the sequencing tasks. We thank Dr Jeremy Stark for providing the pimEJ5GFP (EJ5) plasmid and for his useful discussions. Authors are grateful to Prof Marc‐Andre Langlois, Faculty of Medicine, University of Ottawa, Canada for providing us the A3G RNA‐binding mutants. Funding information: This work was supported by the following grants: The National Institute for Allergy and Infectious Disease (R01AI085015 to SRR), by The Joint Israel‐Canada program (Grant No. 2665/16 MK), by The Milgrom Family Support Fund for projects in Military Medicine (4320614 MK) and partially by the Israel cancer association from the Abraham Rothstein fund (20200084 MK). Funding Information: The authors thank David Ryan for assistance with the mouse breeding. We thank Dr Idit Shiff from the Core Research Facility of the Hebrew University-Hadassah Medical School for the consultation and running the sequencing tasks. We thank Dr Jeremy Stark for providing the pimEJ5GFP (EJ5) plasmid and for his useful discussions. Authors are grateful to Prof Marc-Andre Langlois, Faculty of Medicine, University of Ottawa, Canada for providing us the A3G RNA-binding mutants. Funding information: This work was supported by the following grants: The National Institute for Allergy and Infectious Disease (R01AI085015 to SRR), by The Joint Israel-Canada program (Grant No. 2665/16 MK), by The Milgrom Family Support Fund for projects in Military Medicine (4320614 MK) and partially by the Israel cancer association from the Abraham Rothstein fund (20200084 MK). Publisher Copyright: {\textcopyright} 2022 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.",

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AU - Britan-Rosich, Yelena

AU - Ma, Jing

AU - Kotler, Eran

AU - Hassan, Faizan

AU - Botvinnik, Alexander

AU - Smith, Yoav

AU - Moshel, Ofra

AU - Nasereddin, Abed

AU - Sharma, Gunjan

AU - Pikarsky, Eli

AU - Ross, Susan

AU - Kotler, Moshe

N1 - Funding Information: The authors thank David Ryan for assistance with the mouse breeding. We thank Dr Idit Shiff from the Core Research Facility of the Hebrew University‐Hadassah Medical School for the consultation and running the sequencing tasks. We thank Dr Jeremy Stark for providing the pimEJ5GFP (EJ5) plasmid and for his useful discussions. Authors are grateful to Prof Marc‐Andre Langlois, Faculty of Medicine, University of Ottawa, Canada for providing us the A3G RNA‐binding mutants. Funding information: This work was supported by the following grants: The National Institute for Allergy and Infectious Disease (R01AI085015 to SRR), by The Joint Israel‐Canada program (Grant No. 2665/16 MK), by The Milgrom Family Support Fund for projects in Military Medicine (4320614 MK) and partially by the Israel cancer association from the Abraham Rothstein fund (20200084 MK). Funding Information: The authors thank David Ryan for assistance with the mouse breeding. We thank Dr Idit Shiff from the Core Research Facility of the Hebrew University-Hadassah Medical School for the consultation and running the sequencing tasks. We thank Dr Jeremy Stark for providing the pimEJ5GFP (EJ5) plasmid and for his useful discussions. Authors are grateful to Prof Marc-Andre Langlois, Faculty of Medicine, University of Ottawa, Canada for providing us the A3G RNA-binding mutants. Funding information: This work was supported by the following grants: The National Institute for Allergy and Infectious Disease (R01AI085015 to SRR), by The Joint Israel-Canada program (Grant No. 2665/16 MK), by The Milgrom Family Support Fund for projects in Military Medicine (4320614 MK) and partially by the Israel cancer association from the Abraham Rothstein fund (20200084 MK). Publisher Copyright: © 2022 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

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N2 - Cytosine deaminases AID/APOBEC proteins act as potent nucleic acid editors, playing important roles in innate and adaptive immunity. However, the mutagenic effects of some of these proteins compromise genomic integrity and may promote tumorigenesis. Here, we demonstrate that human APOBEC3G (A3G), in addition to its role in innate immunity, promotes repair of double-strand breaks (DSBs) in vitro and in vivo. Transgenic mice expressing A3G successfully survived lethal irradiation, whereas wild-type controls quickly succumbed to radiation syndrome. Mass spectrometric analyses identified the differential upregulation of a plethora of proteins involved in DSB repair pathways in A3G-expressing cells early following irradiation to facilitate repair. Importantly, we find that A3G not only accelerates DSB repair but also promotes deamination-dependent error-free rejoining. These findings have two implications: (a) strategies aimed at inhibiting A3G may improve the efficacy of genotoxic therapies used to cure malignant tumours; and (b) enhancing A3G activity may reduce acute radiation syndrome in individuals exposed to ionizing radiation.

AB - Cytosine deaminases AID/APOBEC proteins act as potent nucleic acid editors, playing important roles in innate and adaptive immunity. However, the mutagenic effects of some of these proteins compromise genomic integrity and may promote tumorigenesis. Here, we demonstrate that human APOBEC3G (A3G), in addition to its role in innate immunity, promotes repair of double-strand breaks (DSBs) in vitro and in vivo. Transgenic mice expressing A3G successfully survived lethal irradiation, whereas wild-type controls quickly succumbed to radiation syndrome. Mass spectrometric analyses identified the differential upregulation of a plethora of proteins involved in DSB repair pathways in A3G-expressing cells early following irradiation to facilitate repair. Importantly, we find that A3G not only accelerates DSB repair but also promotes deamination-dependent error-free rejoining. These findings have two implications: (a) strategies aimed at inhibiting A3G may improve the efficacy of genotoxic therapies used to cure malignant tumours; and (b) enhancing A3G activity may reduce acute radiation syndrome in individuals exposed to ionizing radiation.

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KW - DNA damage response

KW - DNA repair

KW - cytidine deaminase

KW - homologous recombination

KW - mouse

KW - non-homologous end joining

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APOBEC3G protects the genome of human cultured cells and mice from radiation-induced damage

Abstract

Bibliographical note

Keywords

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