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Characterization of APOBEC3 Family P...

Sasaki, Tomoaki.

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Characterization of APOBEC3 Family Proteins as Potent DNA Mutators in Human Cancers.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Characterization of APOBEC3 Family Proteins as Potent DNA Mutators in Human Cancers./
作者:	Sasaki, Tomoaki.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2018,
面頁冊數:	181 p.
附註:	Source: Dissertations Abstracts International, Volume: 80-02, Section: B.
Contained By:	Dissertations Abstracts International80-02B.
標題:	Pharmacology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10927902
ISBN:	9780438194724

Characterization of APOBEC3 Family Proteins as Potent DNA Mutators in Human Cancers.
Sasaki, Tomoaki.

Characterization of APOBEC3 Family Proteins as Potent DNA Mutators in Human Cancers. - Ann Arbor : ProQuest Dissertations & Theses, 2018 - 181 p.

Source: Dissertations Abstracts International, Volume: 80-02, Section: B.

Thesis (Ph.D.)--Yale University, 2018.

This item must not be added to any third party search indexes.

Apolipoprotein B mRNA Editing Catalytic Polypeptide like 3 (APOBEC3) family proteins are recently discovered cellular cytidine deaminases that collectively play broad physiological roles including lipid transport, antibody diversification, and immunological defense. Until recently, our understanding of this class of DNA mutators has been confined to these roles. However, cancer genome sequencing studies have implicated them in diverse human cancer types through the forrnation of distinct clustered mutations collectively termed APOBEC signatures. Our understanding of the molecular mechanisms underpinning this association is limited to the upregulation of APOBEC3 family proteins at the mRNA level. Detailed investigation of the biochemical and cellular standpoints will be crucial to better understand how APOBEC3 proteins are specifically implicated in cancer. The overall goals of this dissertation involve a multidisciplinary investigation to better characterize APOBEC3 proteins in terms of cytidine deaminase activity, substrate selectivity and specificity, and the identification and validation of putative in vivo targets relevant to cancer. Together, these efforts will reveal important mechanisms by which this novel class of proteins selects and successfully deaminates specific target genes. In the first aim, I conducted a detailed biochemical investigation on requirements at the substrate level for efficient mutagenic APOBEC3B catalysis, which showed that APOBEC3B preferentially deaminates substrates on the basis of multiple factors including primary sequence context, overall length, and stranded nature. This discovery is informative at the in vivo level as it provides mechanistic insights into how APOBEC3 proteins successfully identify their target substrates from a myriad of DNA sequences. In a second method development aim, I designed and optimized a novel ultra high performance liquid chromatography (UHPLC) based assay to detect APOBEC3 activity, the first-in-class assay to directly resolve the ultra fine molecular weight difference of 1 atomic mass unit between the substrate and product of cytidine deamination. The development of such a diversely applicable yet direct assay opens new avenues for complex mechanistic interrogation involving the study of multiple deamination events that likely underpin the formation of clustered APOBEC3 mutations in cancer genomes. In the third and final research aim, I identified and validated putative APOBEC3 targets including the PIK3CA helical domain, the first-in-class study to understand the gene targets that are preferentially deaminated in the context of two human cancers, squamous cell lung carcinoma (SQCLC) and head and neck squamous cell carcinoma (HNSCC). Furthermore, I aimed to assess APOBEC3 activity in clinically relevant cell lines to better characterize their roles in these particular cancers beyond mRNA upregulation. The following studies together converge in the overall goal of understanding how a class of functional DNA mutators exerts its activity on the host genome to drive cancer induction. The multi-pronged investigation presented in this dissertation also sheds new insights on regulation at the protein level, which could be a potential mechanism by which APOBEC3 activity is dysregulated in the context of human cancers. These studies are crucially important in shedding light on how APOBEC3 activity contributes to mutations in critical genes driving cancers, while ultimately shaping mutational landscapes at the cancer genome level.

ISBN: 9780438194724Subjects--Topical Terms:

634543
Pharmacology.

Characterization of APOBEC3 Family Proteins as Potent DNA Mutators in Human Cancers.
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520 $a Apolipoprotein B mRNA Editing Catalytic Polypeptide like 3 (APOBEC3) family proteins are recently discovered cellular cytidine deaminases that collectively play broad physiological roles including lipid transport, antibody diversification, and immunological defense. Until recently, our understanding of this class of DNA mutators has been confined to these roles. However, cancer genome sequencing studies have implicated them in diverse human cancer types through the forrnation of distinct clustered mutations collectively termed APOBEC signatures. Our understanding of the molecular mechanisms underpinning this association is limited to the upregulation of APOBEC3 family proteins at the mRNA level. Detailed investigation of the biochemical and cellular standpoints will be crucial to better understand how APOBEC3 proteins are specifically implicated in cancer. The overall goals of this dissertation involve a multidisciplinary investigation to better characterize APOBEC3 proteins in terms of cytidine deaminase activity, substrate selectivity and specificity, and the identification and validation of putative in vivo targets relevant to cancer. Together, these efforts will reveal important mechanisms by which this novel class of proteins selects and successfully deaminates specific target genes. In the first aim, I conducted a detailed biochemical investigation on requirements at the substrate level for efficient mutagenic APOBEC3B catalysis, which showed that APOBEC3B preferentially deaminates substrates on the basis of multiple factors including primary sequence context, overall length, and stranded nature. This discovery is informative at the in vivo level as it provides mechanistic insights into how APOBEC3 proteins successfully identify their target substrates from a myriad of DNA sequences. In a second method development aim, I designed and optimized a novel ultra high performance liquid chromatography (UHPLC) based assay to detect APOBEC3 activity, the first-in-class assay to directly resolve the ultra fine molecular weight difference of 1 atomic mass unit between the substrate and product of cytidine deamination. The development of such a diversely applicable yet direct assay opens new avenues for complex mechanistic interrogation involving the study of multiple deamination events that likely underpin the formation of clustered APOBEC3 mutations in cancer genomes. In the third and final research aim, I identified and validated putative APOBEC3 targets including the PIK3CA helical domain, the first-in-class study to understand the gene targets that are preferentially deaminated in the context of two human cancers, squamous cell lung carcinoma (SQCLC) and head and neck squamous cell carcinoma (HNSCC). Furthermore, I aimed to assess APOBEC3 activity in clinically relevant cell lines to better characterize their roles in these particular cancers beyond mRNA upregulation. The following studies together converge in the overall goal of understanding how a class of functional DNA mutators exerts its activity on the host genome to drive cancer induction. The multi-pronged investigation presented in this dissertation also sheds new insights on regulation at the protein level, which could be a potential mechanism by which APOBEC3 activity is dysregulated in the context of human cancers. These studies are crucially important in shedding light on how APOBEC3 activity contributes to mutations in critical genes driving cancers, while ultimately shaping mutational landscapes at the cancer genome level.
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