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GENETIC DISSECTION OF FACTORS THAT PROMOTE GENOME STABILITY IN THE CAENORHABDITIS ELEGANS GERM LINE

McClendon, Tiffany Brooke (2016) GENETIC DISSECTION OF FACTORS THAT PROMOTE GENOME STABILITY IN THE CAENORHABDITIS ELEGANS GERM LINE. Doctoral Dissertation, University of Pittsburgh.

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Abstract

Genome stability encompasses the mechanisms that ensure the integrity of DNA is kept intact amidst constant insults, the most toxic of which are DNA double-strand breaks. Deficiencies in factors that detect, respond to, and repair DNA are associated with cancer predisposition and, in some cases, accelerated aging. Maintenance of genome stability is paramount in germ cells, which undergo meiosis to give rise to haploid gametes for reproduction. A key step during meiosis I is the formation of crossovers between homologous chromosomes, which are created by the induction of a DNA double-strand break followed by homologous recombination repair. Crossovers allow homologous chromosomes to segregate such that daughter cells have equal DNA content. Errors stemming from DNA repair or chromosome segregation defects during meiosis are often fatal. Consequently, the process of crossover formation is tightly regulated, though not completely understood. Caenorhabditis elegans offers an advantageous model for studying factors that promote meiotic genome stability, with a well-organized germ line and clear read-outs of defects in DNA repair and chromosome segregation. Here, we explore two factors that promote genome stability in the C. elegans germ line through distinct mechanisms, sws-1 and xnd-1. sws-1 was identified as a potential member of the conserved Shu complex, which promotes homologous recombination by regulating RAD51 filament dynamics. Using a novel allele of sws-1, we found that sws-1 indeed promotes homologous recombination in the germ line, especially at replication forks. Moreover, SWS-1 functions with the RAD-51 paralogs, thus forming a C. elegans Shu complex. Our work provides a new translational model in which to expand our understanding of the Shu complex in a metazoan. xnd-1 was identified as a regulator of meiotic recombination with phenotypes suggestive of a broader role in maintaining genome stability, including sensitivity to ionizing radiation. We found that the high lethality of xnd-1 mutants is not due to chromosome missegregation during meiosis. Rather, our data suggests that the histone acetyltransferase mys-1 may induce genome instability through increased acetylation of histone H2A lysine 5. Our work provides xnd-1 as a model in which to study the link between chromatin factors, gene expression, and genome stability.


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Item Type: University of Pittsburgh ETD
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
McClendon, Tiffany Brooketbm13@pitt.eduTBM13
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorYanowitz, Judith Lyanowitzjl@mwri.magee.eduJLY23
Committee MemberBakkenist, Christopher Jcjb38@pitt.eduCJB38
Committee MemberArndt, Karenarndt@pitt.eduARNDT
Committee MemberVanDemark, Andrew Pandyv@pitt.eduANDYV
Committee MemberBernstein, Karakarab@pitt.eduKARAB
Date: 29 April 2016
Date Type: Publication
Defense Date: 14 March 2016
Approval Date: 29 April 2016
Submission Date: 18 April 2016
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 161
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Molecular Genetics and Developmental Biology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: genome stability, xnd-1, sws-1, Shu complex, DNA, histone, chromatin
Date Deposited: 29 Apr 2016 20:01
Last Modified: 15 Nov 2016 14:32
URI: http://d-scholarship.pitt.edu/id/eprint/27744

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