DNA polymerases as potential therapeutic targets for cancers deficient in the DNA mismatch repair proteins MSH2 or MLH1.
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.
Martin
Sarah A
SA
Cancer Research UK Gene Function and Regulation Group, The Institute of Cancer Research, London SW3 6JB, UK.
McCabe
Nuala
N
Mullarkey
Michelle
M
Cummins
Robert
R
Burgess
Darren J
DJ
Nakabeppu
Yusaku
Y
Oka
Sugako
S
Kay
Elaine
E
Lord
Christopher J
CJ
Ashworth
Alan
A
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D045744:Cell Line, Tumor; D045647:DNA Glycosylases / Q000235:genetics / Q000378:metabolism; D053843:DNA Mismatch Repair; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase / Q000502:physiology; D020868:Gene Silencing; D006151:Guanosine / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics*; D019384:Nucleic Acid Synthesis Inhibitors
D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D006151:Guanosine; C046215:8-hydroxyguanosine; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human; D045647:DNA Glycosylases; C061738:mutY adenine glycosylase; C479058:oxoguanine glycosylase 1, human; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein