PXD020473-2

PXD020473 is an original dataset announced via ProteomeXchange.

Title	The RB/E2F pathway controls expression of the cancer genomic DNA deaminase APOBEC3B
Description	Mutations in cancer are due in part to DNA cytosine deamination by APOBEC3B (A3B). While low in healthy tissues, A3B expression and activity are elevated in tumors and further increase in metastases. However, molecular mechanisms responsible for A3B transcriptional regulation are poorly understood. Here, we address whether the RB/E2F pathway, which is often dysregulated in breast cancer, is a molecular trigger of A3B overexpression. First, an A3B promoter-driven luciferase reporter was used to demonstrate reporter activation by disruption of only one out of five predicted E2F binding sites. Second, A3B-luciferase reporter activation was also triggered by expressing the BK polyomavirus T-antigen, which inactivates RB and thereby alleviates repression of E2F regulated genes. Importantly, A3B-luciferase reporter induction by BK polyomavirus T-antigen could not be further increased by mutating the functional E2F binding site. Third, both CRISPR disruption and targeted base substitutions in the endogenous E2F binding site caused strong A3B upregulation and confirmed importance of this regulatory element. Fourth, proteomics experiments showed that members of the DREAM and PRC1.6-complexes including multiple E2F family members are able to bind to wild-type but not E2F mutant promoter sequences. Finally, a combination of genetic and biochemical studies implicated E2F4 and E2F6 in endogenous A3B gene repression. Altogether, our studies demonstrate that A3B expression is suppressed in normal cells by the RB/E2F axis and that viral or mutational disruption of this pathway causes overexpression of this DNA deaminase in cancer and contributes mutational fuel to tumor evolution.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_05:13:37.758.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Dennis Kappei
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	6x(13)C; 6x(13)C
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2020-07-21 06:52:12	ID requested
1	2021-03-04 12:38:57	announced
⏵ 2	2024-10-22 05:13:45	announced	2024-10-22: Updated project metadata.

10.7554/elife.61287;

Roelofs PA, Goh CY, Chua BH, Jarvis MC, Stewart TA, McCann JL, McDougle RM, Carpenter MA, Martens JW, Span PN, Kappei D, Harris RS, Characterization of the mechanism by which the RB/E2F pathway controls expression of the cancer genomic DNA deaminase APOBEC3B. Elife, 9():(2020) [pubmed]

submitter keyword: cancer, SILAC, DNA pull-down, polyoma virus T antigen,APOBEC3B

Dennis Kappei
contact affiliation	Cancer Science Institute of Singapore (CSI), National University of Singapore (NUS)
contact email	dennis.kappei@nus.edu.sg
lab head
Dennis Kappei
contact affiliation	Cancer Science Institute of Singapore
contact email	dennis.kappei@nus.edu.sg
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD020473
     1. Label: PRIDE project
     2. Name: The RB/E2F pathway controls expression of the cancer genomic DNA deaminase APOBEC3B