A Mechanistic Examination of APOBEC3-Mediated LINE-1 Inhibition.
dc.contributor.author | Richardson, Sandra Rose | en_US |
dc.date.accessioned | 2014-01-16T20:43:54Z | |
dc.date.available | 2014-01-16T20:43:54Z | |
dc.date.issued | 2013 | en_US |
dc.date.submitted | en_US | |
dc.identifier.uri | https://hdl.handle.net/2027.42/102491 | |
dc.description.abstract | Protein-coding genes account for ~3% of the human genome, and a typical gene resides permanently at a discrete chromosomal address. The human genome, however, is not simply a static catalogue of genes; in many ways, it is an ever-changing entity. One dynamic component of the human genome is transposable elements (TEs), or “jumping genes”. Long Interspersed Element-1 (LINE-1 or L1) is a TE whose sequences make up ~17% of human DNA. Although most L1s are inactive, a few retain the ability to mobilize by a process called retrotransposition. L1 is often regarded as a molecular parasite that can be damaging to the host. In fact, ~95 cases of human disease have been attributed to L1-mediated retrotransposition events, and it stands to reason that humans have evolved ways to curtail L1 mobility. The human APOBEC3 (A3) family of cytidine deaminases represents a component of innate immunity hypothesized to have evolved to restrict TE mobility, yet mechanisms by which A3 proteins combat exogenous and endogenous threats are the subject of ongoing study. The focus of my thesis has been a mechanistic examination of A3-mediated L1 inhibition. I have elucidated a mechanism of L1 inhibition by APOBEC3A (A3A), in which A3A deaminates cytidines to uracil in transiently exposed single-stranded DNA during L1 target-site primed reverse transcription (TPRT). In concert with the action of cellular DNA repair factors, which recognize uracil in DNA as damage and degrade deaminated TPRT intermediates, this editing is at least partially responsible for A3A-mediated L1 inhibition. My thesis work represents the first mechanistic explanation for inhibition of an autonomous retroelement by an A3 cytidine deaminase, providing new insight into the dynamic interplay between endogenous retrotransposons and host genomes. | en_US |
dc.language.iso | en_US | en_US |
dc.subject | Retrotransposon | en_US |
dc.subject | APOBEC | en_US |
dc.subject | Cytidine Deaminase | en_US |
dc.subject | Reverse Transcription | en_US |
dc.title | A Mechanistic Examination of APOBEC3-Mediated LINE-1 Inhibition. | en_US |
dc.type | Thesis | en_US |
dc.description.thesisdegreename | PhD | en_US |
dc.description.thesisdegreediscipline | Human Genetics | en_US |
dc.description.thesisdegreegrantor | University of Michigan, Horace H. Rackham School of Graduate Studies | en_US |
dc.contributor.committeemember | Moran, John V. | en_US |
dc.contributor.committeemember | O'Shea, K. Sue | en_US |
dc.contributor.committeemember | Robins, Diane M. | en_US |
dc.contributor.committeemember | Glaser, Thomas M. | en_US |
dc.contributor.committeemember | Chan, Raymond C. | en_US |
dc.subject.hlbsecondlevel | Genetics | en_US |
dc.subject.hlbtoplevel | Science | en_US |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/102491/1/risandra_1.pdf | |
dc.owningcollname | Dissertations and Theses (Ph.D. and Master's) |
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