DNA polymerases as potential therapeutic targets for cancers deficient in the DNA mismatch repair proteins MSH2 or MLH1 (Cancer Cell, 2010, 17:235-248)

報告日期: 2010/10/29
報告時間: 16:00/16:50
報告學生: 吳長霖
講評老師: 黃溫雅
附件下載:

Full text: http://basicmed.med.ncku.edu.tw/admin/up_img/991029-2.pdf

DNA polymerases as potential therapeutic targets for cancers deficient in the DNA mismatch repair proteins MSH2 or MLH1

 

Sarah A. Martin, Nuala McCabe, Michelle Mullarkey, Robert Cummins, Darren J. Burgess, Yusaku Nakabeppu, Sugako Oka, Elaine Kay, Christopher J. Lord and Alan Ashworth

Cancer Cell 17, 235–248, March 16, 2010

 

Speaker: Wu, Chang-Lin

Commentator: Huang, Wen-Ya, Ph.D.

Date: 2010/10/22

Place: Room 602, College of medicine

 

Abstract

Cancer drugs discovery exploit the underlying genetic makeup of tumor cells, such as the efficacy of imatinib (Gleevec) in the BCR-ABL fused leukemias. Although targeting gain-of-function oncogenic events such as the BCR-ABL fusion is conceptually straightforward, it is not obvious how to pharmacologically target a tumor suppressor protein that is dysfunctional or even completely absent. To address this issue, the exploitation of synthetic sickness/lethality (SSL) has been proposed. SSL exists when mutation of either gene alone is compatible with viability but simultaneous mutation of both genes causes death.  According to previous findings, mutations in pol3-01 are SSL with loss of the orthologs of the mismatch repair (MMR) genes EXO1, MSH6, MSH2, MLH1 and PMS2 in budding yeast. It has been demonstrated that SSL relationships involving MLH1 and MSH2 orthologs and DNA polymerase exists in lower organisms, but no SSL relationships were found in human tumor cells yet. In this study, the authors demonstrated whether similar SSL relationships existed in human tumor cells. They demonstrated that deficiency in MSH2 was SSL with inhibition of the DNA polymerase b (POLB), whereas deficiency in MLH1 was SSL with DNA polymerase γ (POLG) inhibition. Moreover, MSH2/POLB SSL caused nuclear 8-oxoguanine (8-oxoG) accumulation, whereas MLH1/POLG SSL led to a rise in mitochondrial 8-oxoG level. Because SSLs could be reduced while silencing the adenine glycosylase MUTYH, the authors further suggested that lethality could be caused by formation of lethal DNA breaks upon 8-oxoG accumulation. In summary, authors provided the proof of principle that SSLs could be exploited to design targeted therapeutic approaches to the treatment of cancers characterized by specific MMR gene defects. Clinical trials of these approaches will require the development of suitable drug-like inhibitors.

 

Reference

1.  Kaelin, W.G., Jr. (2005). The concept of synthetic lethality in the context of anticancer therapy. Nat. Rev. Cancer 5, 689–698.

2.  Macpherson, P., Barone, F., Maga, G., Mazzei, F., Karran, P., and Bignami, M. (2005). 8-oxoguanine incorporation into DNA repeats in vitro and mismatch recognition by MutSa. Nucleic Acids Res. 33, 5094–5105.