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Protein kinase A inhibits tumor mutator APOBEC3B through phosphorylation.

Scientific reports (2019-06-06)
Tadahiko Matsumoto, Kotaro Shirakawa, Masaru Yokoyama, Hirofumi Fukuda, Anamaria Daniela Sarca, Sukenao Koyabu, Hiroyuki Yamazaki, Yasuhiro Kazuma, Hiroyuki Matsui, Wataru Maruyama, Kayoko Nagata, Fumiko Tanabe, Masayuki Kobayashi, Keisuke Shindo, Ryo Morishita, Hironori Sato, Akifumi Takaori-Kondo
ABSTRACT

APOBEC3B cytidine deaminase (A3B) catalyzes cytosine into uracil in single-strand DNA and induces C-to-T mutations in genomic DNA of various types of tumors. Accumulation of APOBEC signature mutations is correlated with a worse prognosis for patients with breast cancer or multiple myeloma, suggesting that A3B activity might be a cause of the unfavorable DNA mutations and clonal evolution in these tumors. Phosphorylation of conserved threonine residues of other cytidine deaminases, activation induced deaminase (AID) and APOBEC3G, inhibits their activity. Here we show that protein kinase A (PKA) physically binds to A3B and phosphorylates Thr214. In vitro deaminase assays and foreign DNA editing assays in cells confirm that phosphomimetic A3B mutants, T214D and T214E, completely lose deaminase activity. Molecular dynamics simulation of A3B phosphorylation reveals that Thr214 phosphorylation disrupts binding between the phospho-A3B catalytic core and ssDNA. These mutants still inhibit retroviral infectivity at least partially, and also retain full anti-retrotransposition activity. These results imply that PKA-mediated phosphorylation inhibits A3B mutagenic activity without destructing its innate immune functions. Therefore, PKA activation could reduce further accumulation of mutations in A3B overexpressing tumors.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Monoclonal ANTI-FLAG® M2 antibody produced in mouse, clone M2, purified immunoglobulin (Purified IgG1 subclass), buffered aqueous solution (10 mM sodium phosphate, 150 mM NaCl, pH 7.4, containing 0.02% sodium azide)
Sigma-Aldrich
Protein Kinase A catalytic subunit human, >90% (SDS-PAGE), recombinant, expressed in E. coli, buffered aqueous glycerol solution

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