TY - CHAP
T1 - Defective DNA Mismatch Repair-dependent c-Abl-p73-GADD45α Expression Confers Cancer Chemoresistance
AU - Li, Long Shan
AU - Wagner, Mark
AU - Meyers, Mark
AU - Boothman, David A.
N1 - Funding Information:
The authors are grateful to Drs James K.V. Willson, Richard Fishel, and Julio Morales for their helpful discussions. This work was supported by NIH/NCI grants R01 CA139217, R01 CA102792 and DOE grant DE-FG02-09ER64789 to DAB. We also thank present and past members of the Boothman laboratory for their helpful discussions of our work on MMR signaling of G 2 cell cycle checkpoint and cell death (apoptotic) responses. This is manuscript CSCN 061 for the Cell Stress and Cancer Nanomedicine Program in the Simmons Comprehensive Cancer Center.
PY - 2012
Y1 - 2012
N2 - This chapter discusses the defective DNA mismatch repair (MRR). DNA mismatch repair (MMR) is a highly conserved repair pathway that plays an important role in the detection and correction of errors created during/after DNA replication (i.e., post-replication repair) and/or after natural genetic recombination events. Genes encoding homologs of bacterial MutS and MutL have been identified in a variety of eukaryotic model systems, including yeast, plants, insects, nematodes, and mammals. In contrast, MMR-deficient cells ignore these DNA lesions, leading to chemoresistance and damage tolerance to O6-meG DNA lesions generated by specific alkylating agents, such as Temozolomide (TMZ). The net effect is the emergence of drug-resistant, highly mutagenic cell populations that progress rapidly to kill the patient. Potential strategies to overcome MMR-deficient mediated chemoresistance based on accumulated evidence were discussed and included the use of agents, such as FdCyd, that can simultaneously hypomethylate an epigenetically silenced hMLH1 promoter resulting in hMLH1 re-expression, and sensitize the emerging cells that have restored MMR capacity.
AB - This chapter discusses the defective DNA mismatch repair (MRR). DNA mismatch repair (MMR) is a highly conserved repair pathway that plays an important role in the detection and correction of errors created during/after DNA replication (i.e., post-replication repair) and/or after natural genetic recombination events. Genes encoding homologs of bacterial MutS and MutL have been identified in a variety of eukaryotic model systems, including yeast, plants, insects, nematodes, and mammals. In contrast, MMR-deficient cells ignore these DNA lesions, leading to chemoresistance and damage tolerance to O6-meG DNA lesions generated by specific alkylating agents, such as Temozolomide (TMZ). The net effect is the emergence of drug-resistant, highly mutagenic cell populations that progress rapidly to kill the patient. Potential strategies to overcome MMR-deficient mediated chemoresistance based on accumulated evidence were discussed and included the use of agents, such as FdCyd, that can simultaneously hypomethylate an epigenetically silenced hMLH1 promoter resulting in hMLH1 re-expression, and sensitize the emerging cells that have restored MMR capacity.
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U2 - 10.1016/B978-0-12-384999-1.10009-5
DO - 10.1016/B978-0-12-384999-1.10009-5
M3 - Chapter
AN - SCOPUS:84882395189
SN - 9780123849991
SP - 191
EP - 210
BT - DNA Repair in Cancer Therapy
PB - Elsevier Inc.
ER -