Dissertation/Thesis Abstract

Keeping L1s in line: Genomic defenses against retrotransposition
by Farkash, Evan A., Ph.D., University of Pennsylvania, 2007, 150; 3261023
Abstract (Summary)

Long Interspersed Elements (L1) are mobile elements responsible for shaping as much as 45% of the human genome. Highly active L1 retrotransposons are agents of genomic instability in vivo. Conversely, L1s might be activated by genomic stress. Here I report on one form of DNA damage, gamma radiation, which is able to increase the retrotransposition frequency of a tagged L1 in tissue culture. Gamma radiation likely enhances L1 mobility by inducing a more favorable cellular environment for endonuclease-dependent retrotransposition. Because L1 mobility is toxic to cells, the survival of an organism may be contingent on its ability to regulate L1 elements. One strategy of L1 regulation is to limit the cell types in which it is active; namely, by restricting L1 expression and retrotransposition to germ cells. New L1 insertions also appear to be subject to regulation. CpG methylation appears to play a role in establishing tissue specific silencing of L1 insertions. L1 insertions are differentially methylated in somatic and germ tissues. Moreover, new L1 insertions are not downregulated in cells grown in tissue culture under demethylating conditions. However, maintenance of L1 repression is likely to involve multiple pathways, as even a toxic dose of demethylating agents is not sufficient to re-express a silenced L1 insertion. DNA methylation is likely to be an important weapon in a cell's arsenal to defend the integrity of the genome against assault by mobile elements.

Indexing (document details)
Advisor:
Commitee:
School: University of Pennsylvania
School Location: United States -- Pennsylvania
Source: DAI-B 68/04, Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Genetics, Immunology
Keywords: Genomic defenses, Long interspersed elements, Retrotransposition
Publication Number: 3261023
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