The DNA deaminase APOBEC3B interacts with the cell-cycle protein CDK4 and disrupts CDK4-mediated nuclear import of cyclin D1

Jennifer L. McCann, Madeline M. Klein, Evelyn M. Leland, Emily K. Law, William L Brown, Daniel J. Salamango, Reuben Harris

Research output: Contribution to journalArticle

Abstract

Apolipoprotein B mRNA editing enzyme catalytic subunit-like protein 3B (APOBEC3B or A3B), as other APOBEC3 members, is a single-stranded (ss)DNA cytosine deaminase with antiviral activity. A3B is also overexpressed in multiple tumor types, such as carcinomas of the bladder, cervix, lung, head/neck, and breast. A3B generates both dispersed and clustered C-to-T and C-to-G mutations in intrinsically preferred trinucleotide motifs (TCA/TCG/TCT). A3B-catalyzed mutations are likely to promote tumor evolution and cancer progression and, as such, are associated with poor clinical outcomes. However, little is known about cellular processes that regulate A3B. Here, we used a proteomics approach involving affinity purification coupled to MS with human 293T cells to identify cellular proteins that interact with A3B. This approach revealed a specific interaction with cyclin-dependent kinase 4 (CDK4). We validated and mapped this interaction by co-immunoprecipitation experiments. Functional studies and immunofluorescence microscopy experiments in multiple cell lines revealed that A3B is not a substrate for CDK4–Cyclin D1 phosphorylation nor is its deaminase activity modulated. Instead, we found that A3B is capable of disrupting the CDK4-dependent nuclear import of Cyclin D1. We propose that this interaction May favor a more potent antiviral response and simultaneously facilitate cancer mutagenesis.

Original languageEnglish (US)
Pages (from-to)12099-12111
Number of pages13
JournalJournal of Biological Chemistry
Volume294
Issue number32
DOIs
StatePublished - Jan 1 2019

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Cyclin-Dependent Kinase 4
Cell Cycle Proteins
Cell Nucleus Active Transport
Cyclin D1
Protein Kinases
Antiviral Agents
Tumors
Cytosine Deaminase
Mutagenesis
Phosphorylation
Single-Stranded DNA
DNA
Apolipoproteins B
Purification
Neoplasms
Microscopic examination
Proteins
Experiments
Cells
Messenger RNA

PubMed: MeSH publication types

  • Journal Article

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The DNA deaminase APOBEC3B interacts with the cell-cycle protein CDK4 and disrupts CDK4-mediated nuclear import of cyclin D1. / McCann, Jennifer L.; Klein, Madeline M.; Leland, Evelyn M.; Law, Emily K.; Brown, William L; Salamango, Daniel J.; Harris, Reuben.

In: Journal of Biological Chemistry, Vol. 294, No. 32, 01.01.2019, p. 12099-12111.

Research output: Contribution to journalArticle

McCann, Jennifer L. ; Klein, Madeline M. ; Leland, Evelyn M. ; Law, Emily K. ; Brown, William L ; Salamango, Daniel J. ; Harris, Reuben. / The DNA deaminase APOBEC3B interacts with the cell-cycle protein CDK4 and disrupts CDK4-mediated nuclear import of cyclin D1. In: Journal of Biological Chemistry. 2019 ; Vol. 294, No. 32. pp. 12099-12111.
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