The role of mismatch repair in mediating cellular sensitivity to cisplatin : the Escherichia coli methyl-directed repair paradigm

The anticancer drug cisplatin is in widespread use but its mechanism of action is only poorly understood. Moreover, human cancers acquire resistance to the drug, which limits its clinical utility. A paradox in the field is how loss of mismatch DNA repair leads to clinical resistance to this widely used drug. The phenomenon of cisplatin tolerance in mismatch repair deficient cells was initially discovered in E. coli, where methylation deficient dam mutants show high sensitivity to cisplatin and dam mutants with an additional mutation in either of the mismatch repair genes mutS or mutL show near wildtype levels of resistance. A prevalent explanation for this observation is the abortive repair model, which proposes that in dam mutants, where the strand discrimination signal is lost, mismatch repair attempts futile cycles of repair opposite cisplatin-DNA adducts. Previous findings have supported this model to the extent that MutS, the E. coli mismatch recognition protein, specifically recognizes DNA modified with cisplatin. However it has recently been shown that MutS binding to cisplatin adducts may contribute to toxicity by instead preventing the recombinational repair of a cisplatin-modified substrate, and we have previously shown that recombination is an essential mechanism for tolerating cisplatin damage.

Department dc:contributor.department

Massachusetts Institute of Technology. Biological Engineering Division.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2006

Author dc:creator

• Robbins, Jennifer L

Advisor dc:contributor.advisor

• John M. Essigmann.

• 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/1721.1/34155
• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Identifier URI

http://dspace.mit.edu/handle/1721.1/34155

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/34155