Molecular basis of the attenuated phenotype of human APOBEC3B DNA mutator enzyme

Caval, Vincent; Bouzidi, Mohamed S.; Suspène, Rodolphe; Laude, Hélène; Dumargne, Marie-Charlotte; Bashamboo, Anu; Krey, Thomas; Vartanian, Jean‐Pierre; Wain‐Hobson, Simon

doi:10.1093/nar/gkv935

Cited by 31 publications

(38 citation statements)

References 38 publications

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“…Interestingly, regional clusters of strand-coordinated hypermutation (C>T and/or C>G mutations), termed “kataegis” (Greek word for thunderstorm) 75 , in the context of TpC dinucleotides were commonly observed in breast 75,78–80 and other cancers 76–79,81 . Although A3A alone is able to induce double-strand DNA breaks 69,82–84 , both A3A 80,81 and A3B 31,33,70,81,85,86 (also see review in ref. 87 ) contribute to mutational effects in tumor genomes.…”

Section: Introductionmentioning

confidence: 99%

Nuclear Magnetic Resonance Structure of the APOBEC3B Catalytic Domain: Structural Basis for Substrate Binding and DNA Deaminase Activity

Byeon¹,

Byeon²,

et al. 2016

Biochemistry

103

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Human APOBEC3B (A3B) is a member of the APOBEC3 (A3) family of cytidine deaminases, which function as DNA mutators and restrict viral pathogens and endogenous retrotransposons. Recently, A3B was identified as a major source of genetic heterogeneity in several human cancers. Here, we determined the solution NMR structure of the catalytically active C-terminal domain (CTD) of A3B and performed detailed analyses of its deaminase activity. The core of the structure comprises a central five-stranded β-sheet with six surrounding helices, common to all A3 proteins. The structural fold is most similar to that of A3A and A3G-CTD, with the most prominent difference found in loop 1. The catalytic activity of A3B-CTD is ~15-fold less than that of A3A, although both exhibit similar pH dependence. Interestingly, A3B-CTD with an A3A loop 1 substitution had significantly increased deaminase activity, while a single residue change (H29R) in A3A loop 1 reduced A3A activity to the level seen with A3B-CTD. This establishes that loop 1 plays an important role in A3-catalyzed deamination by precisely positioning the deamination-targeted C into the active site. Overall, our data provide important insights into the determinants for the activities of individual A3 proteins and facilitate understanding of their biological function.

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Section: Introductionmentioning

confidence: 99%

Nuclear Magnetic Resonance Structure of the APOBEC3B Catalytic Domain: Structural Basis for Substrate Binding and DNA Deaminase Activity

Byeon¹,

Byeon²,

et al. 2016

Biochemistry

103

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“…Aberrant APOBEC-3B (A3B) deaminase activity has been suggested as a likely cause of single-base substitution in cancer because A3B is often up-regulated in cancer and its preferred target sequence (TC) is frequently mutated and clustered in multiple human cancers (16 -20). Both A3A and A3B can actually induce base substitutions in the DNA genome when transfected into cells (21)(22)(23). APOBEC-3s (A, B, C, D, F, G, and H) are zinc-dependent cytidine deaminases that catalyze the conversion of cytidine to uracil in single-stranded DNA (24,25).…”

mentioning

confidence: 99%

Heat shock proteins stimulate APOBEC-3–mediated cytidine deamination in the hepatitis B virus

Chen¹,

Eggerman

Bocharov³

et al. 2017

Journal of Biological Chemistry

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Apolipoprotein B mRNA-editing enzyme catalytic subunit 3 (APOBEC-3) enzymes are cytidine deaminases that are broadly and constitutively expressed. They are often up-regulated during carcinogenesis and candidate genes for causing the major single-base substitution in cancer-associated DNA mutations. Moreover, APOBEC-3s are involved in host innate immunity against many viruses. However, how APOBEC-3 mutational activity is regulated in normal and pathological conditions remains largely unknown. Heat shock protein levels are often elevated in both carcinogenesis and viral infection and are associated with DNA mutations. Here, using mutational analyses of hepatitis B virus (HBV), we found that Hsp90 stimulates deamination activity of APOBEC-3G (A3G), A3B, and A3C during co-expression in human liver HepG2 cells. Hsp90 directly stimulated A3G deamination activity when the purified proteins were used in reactions. Hsp40, -60, and -70 also had variable stimulatory effects in the cellular assay, but not Sequencing analyses further demonstrated that Hsp90 increased both A3G cytosine mutation efficiency on HBV DNA and total HBV mutation frequency. In addition, Hsp90 shifted A3G's cytosine region selection in HBV DNA and increased A3G's 5' nucleoside preference for deoxycytidine (5'-CC). Furthermore, the Hsp90 inhibitor 17--allylamino-17-demethoxygeldanamycin dose dependently inhibited A3G and A3B mutational activity on HBV viral DNA. Hsp90 knockdown by siRNA or by Hsp90 active-site mutation also decreased A3G activity. These results indicate that heat shock proteins, in particular Hsp90, stimulate APOBEC-3-mediated DNA deamination activity, suggesting a potential physiological role in carcinogenesis and viral innate immunity.

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“…Moreover, APOBEC3A (A3A) has also been implicated through a number of lines of investigation but studies on the endogenous enzyme have yet to be done in model systems due to low/no expression (e.g., refs. 23,[38][39][40][41][42][43][44][45][46] ). Ongoing research by many groups is likely to clarify the relative contributions of each APOBEC enzyme to mutagenesis in different tumor types, and new technologies and reagents including validated monoclonal antibodies (mAbs) are likely to have essential roles in this process.…”

Section: Virologymentioning

confidence: 99%

A rabbit monoclonal antibody against the antiviral and cancer genomic DNA mutating enzyme APOBEC3B

Brown

Law

Carpenter

et al. 2019

Preprint

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The DNA cytosine deaminase APOBEC3B (A3B) is normally an antiviral factor in the innate immune response. However, A3B has been implicated in cancer mutagenesis, particularly in solid tumors of the bladder, breast, cervix, head/neck, and lung. Here, we report data on the generation and characterization of a rabbit monoclonal antibody (mAb) for human A3B through a series of immunoblot, immunofluorescence microscopy, and immunohistochemistry experiments. Positive results indicate that one mAb, 5210-87-13, will be useful for fundamental research in virology and cancer biology and that immunohistochemical quantification of A3B enzyme levels may constitute a clinical biomarker for tumor evolvability and differential treatment.

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Molecular basis of the attenuated phenotype of human APOBEC3B DNA mutator enzyme

Cited by 31 publications

References 38 publications

Nuclear Magnetic Resonance Structure of the APOBEC3B Catalytic Domain: Structural Basis for Substrate Binding and DNA Deaminase Activity

Nuclear Magnetic Resonance Structure of the APOBEC3B Catalytic Domain: Structural Basis for Substrate Binding and DNA Deaminase Activity

Heat shock proteins stimulate APOBEC-3–mediated cytidine deamination in the hepatitis B virus

A rabbit monoclonal antibody against the antiviral and cancer genomic DNA mutating enzyme APOBEC3B

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