Substrate sequence selectivity of APOBEC3A implicates intra-DNA interactions

Abstract The APOBEC3 (A3) family of human cytidine deaminases is renowned for providing a first line of defense against many exogenous and endogenous retroviruses. However, the ability of these proteins to deaminate deoxycytidines in ssDNA makes A3s a double-edged sword. When overexpressed, A3s can...

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Autores principales:	Tania V. Silvas, Shurong Hou, Wazo Myint, Ellen Nalivaika, Mohan Somasundaran, Brian A. Kelch, Hiroshi Matsuo, Nese Kurt Yilmaz, Celia A. Schiffer
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/0666f6b6aeeb4da28babab14046087f4
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spelling	oai:doaj.org-article:0666f6b6aeeb4da28babab14046087f42021-12-02T12:32:11ZSubstrate sequence selectivity of APOBEC3A implicates intra-DNA interactions10.1038/s41598-018-25881-z2045-2322https://doaj.org/article/0666f6b6aeeb4da28babab14046087f42018-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-25881-zhttps://doaj.org/toc/2045-2322Abstract The APOBEC3 (A3) family of human cytidine deaminases is renowned for providing a first line of defense against many exogenous and endogenous retroviruses. However, the ability of these proteins to deaminate deoxycytidines in ssDNA makes A3s a double-edged sword. When overexpressed, A3s can mutate endogenous genomic DNA resulting in a variety of cancers. Although the sequence context for mutating DNA varies among A3s, the mechanism for substrate sequence specificity is not well understood. To characterize substrate specificity of A3A, a systematic approach was used to quantify the affinity for substrate as a function of sequence context, length, secondary structure, and solution pH. We identified the A3A ssDNA binding motif as (T/C)TC(A/G), which correlated with enzymatic activity. We also validated that A3A binds RNA in a sequence specific manner. A3A bound tighter to substrate binding motif within a hairpin loop compared to linear oligonucleotide, suggesting A3A affinity is modulated by substrate structure. Based on these findings and previously published A3A–ssDNA co-crystal structures, we propose a new model with intra-DNA interactions for the molecular mechanism underlying A3A sequence preference. Overall, the sequence and structural preferences identified for A3A leads to a new paradigm for identifying A3A’s involvement in mutation of endogenous or exogenous DNA.Tania V. SilvasShurong HouWazo MyintEllen NalivaikaMohan SomasundaranBrian A. KelchHiroshi MatsuoNese Kurt YilmazCelia A. SchifferNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-11 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Tania V. Silvas Shurong Hou Wazo Myint Ellen Nalivaika Mohan Somasundaran Brian A. Kelch Hiroshi Matsuo Nese Kurt Yilmaz Celia A. Schiffer Substrate sequence selectivity of APOBEC3A implicates intra-DNA interactions
description	Abstract The APOBEC3 (A3) family of human cytidine deaminases is renowned for providing a first line of defense against many exogenous and endogenous retroviruses. However, the ability of these proteins to deaminate deoxycytidines in ssDNA makes A3s a double-edged sword. When overexpressed, A3s can mutate endogenous genomic DNA resulting in a variety of cancers. Although the sequence context for mutating DNA varies among A3s, the mechanism for substrate sequence specificity is not well understood. To characterize substrate specificity of A3A, a systematic approach was used to quantify the affinity for substrate as a function of sequence context, length, secondary structure, and solution pH. We identified the A3A ssDNA binding motif as (T/C)TC(A/G), which correlated with enzymatic activity. We also validated that A3A binds RNA in a sequence specific manner. A3A bound tighter to substrate binding motif within a hairpin loop compared to linear oligonucleotide, suggesting A3A affinity is modulated by substrate structure. Based on these findings and previously published A3A–ssDNA co-crystal structures, we propose a new model with intra-DNA interactions for the molecular mechanism underlying A3A sequence preference. Overall, the sequence and structural preferences identified for A3A leads to a new paradigm for identifying A3A’s involvement in mutation of endogenous or exogenous DNA.
format	article
author	Tania V. Silvas Shurong Hou Wazo Myint Ellen Nalivaika Mohan Somasundaran Brian A. Kelch Hiroshi Matsuo Nese Kurt Yilmaz Celia A. Schiffer
author_facet	Tania V. Silvas Shurong Hou Wazo Myint Ellen Nalivaika Mohan Somasundaran Brian A. Kelch Hiroshi Matsuo Nese Kurt Yilmaz Celia A. Schiffer
author_sort	Tania V. Silvas
title	Substrate sequence selectivity of APOBEC3A implicates intra-DNA interactions
title_short	Substrate sequence selectivity of APOBEC3A implicates intra-DNA interactions
title_full	Substrate sequence selectivity of APOBEC3A implicates intra-DNA interactions
title_fullStr	Substrate sequence selectivity of APOBEC3A implicates intra-DNA interactions
title_full_unstemmed	Substrate sequence selectivity of APOBEC3A implicates intra-DNA interactions
title_sort	substrate sequence selectivity of apobec3a implicates intra-dna interactions
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/0666f6b6aeeb4da28babab14046087f4
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Substrate sequence selectivity of APOBEC3A implicates intra-DNA interactions

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