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Protecting the Genome: Preserving Nu...

Buzovetsky, Olga.

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Protecting the Genome: Preserving Nucleotide Metabolism and DNA Repair, and Defending Against Viral Invaders.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Protecting the Genome: Preserving Nucleotide Metabolism and DNA Repair, and Defending Against Viral Invaders./
作者:	Buzovetsky, Olga.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2018,
面頁冊數:	161 p.
附註:	Source: Dissertations Abstracts International, Volume: 80-08, Section: B.
Contained By:	Dissertations Abstracts International80-08B.
標題:	Biochemistry. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=13841637
ISBN:	9780438902510

Protecting the Genome: Preserving Nucleotide Metabolism and DNA Repair, and Defending Against Viral Invaders.
Buzovetsky, Olga.

Protecting the Genome: Preserving Nucleotide Metabolism and DNA Repair, and Defending Against Viral Invaders. - Ann Arbor : ProQuest Dissertations & Theses, 2018 - 161 p.

Source: Dissertations Abstracts International, Volume: 80-08, Section: B.

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

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

Genome integrity is fundamentally important for human health. Various human diseases, including cancers and autoimmune diseases, are caused by the dysregulation of mechanisms that preserve the genetic code. Understanding how the genome is regulated in disease necessitates studying these mechanisms at a molecular level. The first stage of cellular maintenance is proper metabolism of nucleotides. SAMHD1, an enzyme that degrades dNTPs into their component nucleoside and inorganic triphosphates, contributes to the overall balance of dNTPs in the cell. Therefore, it is important to understand how full-length SAMHD1 is activated and regulated. We crystallized the first full-length structure of mouse SAMHD1 that captured the interactions between the HAD and the SAM domains that are necessary for its function. We determined the crystal structures of three states along the activation pathway of mouse SAMHD1 that captured how mouse SAMHD1 requires the SAM domain for its activity and regulation. Interestingly, SAMHD1 activity has been linked to low efficacy of cancer drugs. Since SAMHD1 requires bound dNTPs for allosteric activation and hydrolysis, we elected to study how SAMHD1 selects nucleotide analogue drugs that mimic canonical dNTPs. We crystallized SAMHD1 with nucleotide analogues bound to the allosteric and catalytic sites. These structures revealed the more restrictive nature of the allosteric site compared to the catalytic site. Results from this study can improve current nucleotide analogue therapies, such as ensuring that novel drugs have sufficient sugar modifications to allow them to evade turnover by SAMHD1 in the cell. In addition to maintenance of the cellular nucleotide pool, DNA repair is essential for genome fidelity. The least understood double strand break (DSB) repair pathway is the repair of single-ended DNA double-strand breaks by break-induced replication (BIR), a conserved homologous recombination pathway. To understand the interactions necessary for proper repair, we examined the complex formation between the helicase Pif1 and PCNA, a DNA clamp. We identified a non-canonical PIP-box in the C-terminus of Pif1 that mediates the interaction between Pif1 and PCNA. Mutations in this region abolish binding to PCNA, which consequently lead to defects in BIR. Finally, pathogens such as Epstein Barr Virus (EBV) attack the host genome and cause various human cancers. Specifically, their conversion from latent to lytic phase through the interaction of ZEBRA transcription factor with methylated promoters triggers disease development. To understand how ZEBRA recognizes methylated promoter sequences in DNA, we examined the regions of ZEBRA necessary for DNA binding. We found a positively charged region upstream of the canonical DNA binding domain that is essential for high-affinity DNA binding and recognition of the DNA methylation state, and, ultimately, lytic cycle activation. Throughout the species lifetime, the integrity of its genome is continuously under threat. Thus the fundamental goal of the cellular machinery is to preserve the integrity of the genome to ensure progeny receive accurate information. With the help from various cellular maintenance and repair mechanisms the cell protects the integrity of its genome.

ISBN: 9780438902510Subjects--Topical Terms:

518028
Biochemistry.

Protecting the Genome: Preserving Nucleotide Metabolism and DNA Repair, and Defending Against Viral Invaders.
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520 $a Genome integrity is fundamentally important for human health. Various human diseases, including cancers and autoimmune diseases, are caused by the dysregulation of mechanisms that preserve the genetic code. Understanding how the genome is regulated in disease necessitates studying these mechanisms at a molecular level. The first stage of cellular maintenance is proper metabolism of nucleotides. SAMHD1, an enzyme that degrades dNTPs into their component nucleoside and inorganic triphosphates, contributes to the overall balance of dNTPs in the cell. Therefore, it is important to understand how full-length SAMHD1 is activated and regulated. We crystallized the first full-length structure of mouse SAMHD1 that captured the interactions between the HAD and the SAM domains that are necessary for its function. We determined the crystal structures of three states along the activation pathway of mouse SAMHD1 that captured how mouse SAMHD1 requires the SAM domain for its activity and regulation. Interestingly, SAMHD1 activity has been linked to low efficacy of cancer drugs. Since SAMHD1 requires bound dNTPs for allosteric activation and hydrolysis, we elected to study how SAMHD1 selects nucleotide analogue drugs that mimic canonical dNTPs. We crystallized SAMHD1 with nucleotide analogues bound to the allosteric and catalytic sites. These structures revealed the more restrictive nature of the allosteric site compared to the catalytic site. Results from this study can improve current nucleotide analogue therapies, such as ensuring that novel drugs have sufficient sugar modifications to allow them to evade turnover by SAMHD1 in the cell. In addition to maintenance of the cellular nucleotide pool, DNA repair is essential for genome fidelity. The least understood double strand break (DSB) repair pathway is the repair of single-ended DNA double-strand breaks by break-induced replication (BIR), a conserved homologous recombination pathway. To understand the interactions necessary for proper repair, we examined the complex formation between the helicase Pif1 and PCNA, a DNA clamp. We identified a non-canonical PIP-box in the C-terminus of Pif1 that mediates the interaction between Pif1 and PCNA. Mutations in this region abolish binding to PCNA, which consequently lead to defects in BIR. Finally, pathogens such as Epstein Barr Virus (EBV) attack the host genome and cause various human cancers. Specifically, their conversion from latent to lytic phase through the interaction of ZEBRA transcription factor with methylated promoters triggers disease development. To understand how ZEBRA recognizes methylated promoter sequences in DNA, we examined the regions of ZEBRA necessary for DNA binding. We found a positively charged region upstream of the canonical DNA binding domain that is essential for high-affinity DNA binding and recognition of the DNA methylation state, and, ultimately, lytic cycle activation. Throughout the species lifetime, the integrity of its genome is continuously under threat. Thus the fundamental goal of the cellular machinery is to preserve the integrity of the genome to ensure progeny receive accurate information. With the help from various cellular maintenance and repair mechanisms the cell protects the integrity of its genome.
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