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

J Biol Chem

Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota 55455; Institute for Molecular Virology, University of Minnesota, Minneapolis, Minnesota 55455; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455; Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota 55455; Howard Hughes Medical Institute, University of Minnesota, Minneapolis, Minnesota 55455. Electronic address:

Published: August 2019

AI Article Synopsis

  • APOBEC3B (A3B) is a protein that edits DNA, exhibiting antiviral properties and is found at high levels in various cancers, potentially contributing to tumor evolution and poor outcomes.
  • Research using human cell lines identified a specific interaction between A3B and cyclin-dependent kinase 4 (CDK4), revealing that A3B does not get phosphorylated by CDK4 nor does it affect its enzymatic activity.
  • Instead, A3B inhibits the nuclear import of Cyclin D1, which may enhance antiviral responses while promoting mutations in cancer, leading to a dual role in cellular processes.

Article 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 (TA/TG/TT). 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.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6690700PMC
http://dx.doi.org/10.1074/jbc.RA119.008443DOI Listing

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