TY - JOUR
T1 - DNA Polymerases as Potential Therapeutic Targets for Cancers Deficient in the DNA Mismatch Repair Proteins MSH2 or MLH1
AU - Martin, Sarah A.
AU - McCabe, Nuala
AU - Mullarkey, Michelle
AU - Cummins, Robert
AU - Burgess, Darren J.
AU - Nakabeppu, Yusaku
AU - Oka, Sugako
AU - Kay, Elaine
AU - Lord, Christopher J.
AU - Ashworth, Alan
N1 - Funding Information:
We thank Dr. T. Kunkel, Dr. A. Clark, and Dr. R. Brown for the provision of cell lines. We thank Dr. C. Cazaux and Dr. G. Massiot for providing masticadienonic acid. We also thank Dr. M. Hewish for helpful discussions. C.J.L., A.A., and S.A.M. are inventors on a patent pertaining to this work and may financially gain under the ICR rewards to investors scheme. This work was supported by grants from Cancer Research UK and Breakthrough Breast Cancer. We acknowledge NHS funding to the NIHR Biomedical Research Centre.
PY - 2010/3/16
Y1 - 2010/3/16
N2 - Synthetic sickness/lethality (SSL) can be exploited to develop therapeutic strategies for cancer. Deficiencies in the tumor suppressor proteins MLH1 and MSH2 have been implicated in cancer. Here we demonstrate that deficiency in MSH2 is SSL with inhibition of the DNA polymerase POLB, whereas deficiency in MLH1 is SSL with DNA polymerase POLG inhibition. Both SSLs led to the accumulation of 8-oxoG oxidative DNA lesions. MSH2/POLB SSL caused nuclear 8-oxoG accumulation, whereas MLH1/POLG SSL led to a rise in mitochondrial 8-oxoG levels. Both SSLs were rescued by silencing the adenine glycosylase MUTYH, suggesting that lethality could be caused by the formation of lethal DNA breaks upon 8-oxoG accumulation. These data suggest targeted, mechanism-based therapeutic approaches.
AB - Synthetic sickness/lethality (SSL) can be exploited to develop therapeutic strategies for cancer. Deficiencies in the tumor suppressor proteins MLH1 and MSH2 have been implicated in cancer. Here we demonstrate that deficiency in MSH2 is SSL with inhibition of the DNA polymerase POLB, whereas deficiency in MLH1 is SSL with DNA polymerase POLG inhibition. Both SSLs led to the accumulation of 8-oxoG oxidative DNA lesions. MSH2/POLB SSL caused nuclear 8-oxoG accumulation, whereas MLH1/POLG SSL led to a rise in mitochondrial 8-oxoG levels. Both SSLs were rescued by silencing the adenine glycosylase MUTYH, suggesting that lethality could be caused by the formation of lethal DNA breaks upon 8-oxoG accumulation. These data suggest targeted, mechanism-based therapeutic approaches.
UR - http://www.scopus.com/inward/record.url?scp=77649311945&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77649311945&partnerID=8YFLogxK
U2 - 10.1016/j.ccr.2009.12.046
DO - 10.1016/j.ccr.2009.12.046
M3 - Article
C2 - 20227038
AN - SCOPUS:77649311945
SN - 1535-6108
VL - 17
SP - 235
EP - 248
JO - Cancer Cell
JF - Cancer Cell
IS - 3
ER -
