Characterization of the mechanism by which the RB/E2F pathway controls expression of the cancer genomic DNA deaminase APOBEC3B
APOBEC3B (A3B)-catalyzed DNA cytosine deamination contributes to the overall mutational landscape in breast cancer. Molecular mechanisms responsible for A3B upregulation in cancer are poorly understood. Here we show that a single E2F cis-element mediates repression in normal cells and that expressio...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2020-09-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/61287 |
| _version_ | 1811252884190265344 |
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| author | Pieter A Roelofs Chai Yeen Goh Boon Haow Chua Matthew C Jarvis Teneale A Stewart Jennifer L McCann Rebecca M McDougle Michael A Carpenter John WM Martens Paul N Span Dennis Kappei Reuben S Harris |
| author_facet | Pieter A Roelofs Chai Yeen Goh Boon Haow Chua Matthew C Jarvis Teneale A Stewart Jennifer L McCann Rebecca M McDougle Michael A Carpenter John WM Martens Paul N Span Dennis Kappei Reuben S Harris |
| author_sort | Pieter A Roelofs |
| collection | DOAJ |
| description | APOBEC3B (A3B)-catalyzed DNA cytosine deamination contributes to the overall mutational landscape in breast cancer. Molecular mechanisms responsible for A3B upregulation in cancer are poorly understood. Here we show that a single E2F cis-element mediates repression in normal cells and that expression is activated by its mutational disruption in a reporter construct or the endogenous A3B gene. The same E2F site is required for A3B induction by polyomavirus T antigen indicating a shared molecular mechanism. Proteomic and biochemical experiments demonstrate the binding of wildtype but not mutant E2F promoters by repressive PRC1.6/E2F6 and DREAM/E2F4 complexes. Knockdown and overexpression studies confirm the involvement of these repressive complexes in regulating A3B expression. Altogether, these studies demonstrate that A3B expression is suppressed in normal cells by repressive E2F complexes and that viral or mutational disruption of this regulatory network triggers overexpression in breast cancer and provides fuel for tumor evolution. |
| first_indexed | 2024-04-12T16:42:18Z |
| format | Article |
| id | doaj.art-562661be3bbb4115a4d955575847fc12 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T16:42:18Z |
| publishDate | 2020-09-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-562661be3bbb4115a4d955575847fc122022-12-22T03:24:44ZengeLife Sciences Publications LtdeLife2050-084X2020-09-01910.7554/eLife.61287Characterization of the mechanism by which the RB/E2F pathway controls expression of the cancer genomic DNA deaminase APOBEC3BPieter A Roelofs0https://orcid.org/0000-0002-4921-7089Chai Yeen Goh1Boon Haow Chua2Matthew C Jarvis3Teneale A Stewart4https://orcid.org/0000-0003-4837-9315Jennifer L McCann5https://orcid.org/0000-0003-0458-1335Rebecca M McDougle6Michael A Carpenter7John WM Martens8https://orcid.org/0000-0002-3428-3366Paul N Span9https://orcid.org/0000-0002-1930-6638Dennis Kappei10https://orcid.org/0000-0002-3582-2253Reuben S Harris11https://orcid.org/0000-0002-9034-9112Department of Biochemistry, Molecular Biology and Biophysics, Masonic Cancer Center, Institute for Molecular Virology, Center for Genome Engineering, University of Minnesota, Minneapolis, United States; Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, NetherlandsCancer Science Institute of Singapore, National University of Singapore, Singapore, SingaporeCancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, SingaporeDepartment of Biochemistry, Molecular Biology and Biophysics, Masonic Cancer Center, Institute for Molecular Virology, Center for Genome Engineering, University of Minnesota, Minneapolis, United StatesDepartment of Biochemistry, Molecular Biology and Biophysics, Masonic Cancer Center, Institute for Molecular Virology, Center for Genome Engineering, University of Minnesota, Minneapolis, United States; Mater Research Institute, The University of Queensland, Faculty of Medicine, Brisbane, AustraliaDepartment of Biochemistry, Molecular Biology and Biophysics, Masonic Cancer Center, Institute for Molecular Virology, Center for Genome Engineering, University of Minnesota, Minneapolis, United States; Howard Hughes Medical Institute, University of Minnesota, Minneapolis, United StatesDepartment of Biochemistry, Molecular Biology and Biophysics, Masonic Cancer Center, Institute for Molecular Virology, Center for Genome Engineering, University of Minnesota, Minneapolis, United States; Hennepin Healthcare, Minneapolis, United StatesDepartment of Biochemistry, Molecular Biology and Biophysics, Masonic Cancer Center, Institute for Molecular Virology, Center for Genome Engineering, University of Minnesota, Minneapolis, United States; Howard Hughes Medical Institute, University of Minnesota, Minneapolis, United StatesErasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, NetherlandsDepartment of Radiation Oncology, Radboud University Medical Center, Nijmegen, NetherlandsCancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, SingaporeDepartment of Biochemistry, Molecular Biology and Biophysics, Masonic Cancer Center, Institute for Molecular Virology, Center for Genome Engineering, University of Minnesota, Minneapolis, United States; Howard Hughes Medical Institute, University of Minnesota, Minneapolis, United StatesAPOBEC3B (A3B)-catalyzed DNA cytosine deamination contributes to the overall mutational landscape in breast cancer. Molecular mechanisms responsible for A3B upregulation in cancer are poorly understood. Here we show that a single E2F cis-element mediates repression in normal cells and that expression is activated by its mutational disruption in a reporter construct or the endogenous A3B gene. The same E2F site is required for A3B induction by polyomavirus T antigen indicating a shared molecular mechanism. Proteomic and biochemical experiments demonstrate the binding of wildtype but not mutant E2F promoters by repressive PRC1.6/E2F6 and DREAM/E2F4 complexes. Knockdown and overexpression studies confirm the involvement of these repressive complexes in regulating A3B expression. Altogether, these studies demonstrate that A3B expression is suppressed in normal cells by repressive E2F complexes and that viral or mutational disruption of this regulatory network triggers overexpression in breast cancer and provides fuel for tumor evolution.https://elifesciences.org/articles/61287APOBEC3Bcancer mutagenesisDREAM complexPRC1.6 complexRB/E2F pathwaytranscriptional regulation |
| spellingShingle | Pieter A Roelofs Chai Yeen Goh Boon Haow Chua Matthew C Jarvis Teneale A Stewart Jennifer L McCann Rebecca M McDougle Michael A Carpenter John WM Martens Paul N Span Dennis Kappei Reuben S Harris Characterization of the mechanism by which the RB/E2F pathway controls expression of the cancer genomic DNA deaminase APOBEC3B eLife APOBEC3B cancer mutagenesis DREAM complex PRC1.6 complex RB/E2F pathway transcriptional regulation |
| title | Characterization of the mechanism by which the RB/E2F pathway controls expression of the cancer genomic DNA deaminase APOBEC3B |
| title_full | Characterization of the mechanism by which the RB/E2F pathway controls expression of the cancer genomic DNA deaminase APOBEC3B |
| title_fullStr | Characterization of the mechanism by which the RB/E2F pathway controls expression of the cancer genomic DNA deaminase APOBEC3B |
| title_full_unstemmed | Characterization of the mechanism by which the RB/E2F pathway controls expression of the cancer genomic DNA deaminase APOBEC3B |
| title_short | Characterization of the mechanism by which the RB/E2F pathway controls expression of the cancer genomic DNA deaminase APOBEC3B |
| title_sort | characterization of the mechanism by which the rb e2f pathway controls expression of the cancer genomic dna deaminase apobec3b |
| topic | APOBEC3B cancer mutagenesis DREAM complex PRC1.6 complex RB/E2F pathway transcriptional regulation |
| url | https://elifesciences.org/articles/61287 |
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