Mitotic homologous recombination at engineered repeats in S. cerevisiae and in novel transgenic mice

Although homologous recombination provides an efficient means for repairing and tolerating DNA damage, mitotic recombination between misaligned sequences can lead to loss of genetic information (e.g. deletions, translocations and loss of heterozygosity). Given that such genetic changes may promote tumorigenesis, it is critical to identify those genetic and environmental factors that render cells susceptible to homologous recombination. Our goal is to elucidate the mechanisms of DNA damage-induced recombination and to determine the role of DNA repair enzymes in modulating homologous recombination in eukaryotic cells. Alkylating agents are abundant in our environment and are generated endogenously as normal metabolites. In addition to their mutagenic and cytotoxic effects, alkylating agents stimulate homologous recombination in eukaryotic cells. Removal of alkylated bases by DNA glycosylases, such as the Magl 3-methyladenine (3MeA) DNA glycosylase, initiates the base excision repair (BER) pathway. To investigate the molecular basis for methylation-induced homologous recombination in S. cerevisiae, intrachromosomal recombination was measured under conditions where MAGI expression levels were varied. Cells lacking Magl show increased susceptibility to methylation-induced recombination, suggesting that unrepaired 3MeA lesions induce recombination. Overexpression of M4GI also elevates recombination levels, presumably due to the accumulation of recombinogenic BER intermediates.

Department dc:contributor.department

Massachusetts Institute of Technology. Biological Engineering Division.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2003

Author dc:creator

• Hendricks, Carrie A. (Carrie Anne), 1975-

Advisor dc:contributor.advisor

• Bevin P. Engelward.

• Biological Engineering Division.

Statement dc:rights

• MIT theses are protected by copyright. They may be viewed, downloaded, or printed from this source but further reproduction or distribution in any format is prohibited without written permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/29615

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/29615