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DNA Polymerases as Potential Therapeutic Targets for Cancers Deficient in the DNA Mismatch Repair Proteins MSH2 or MLH1

Cancer Cell, ISSN: 1535-6108, Vol: 17, Issue: 3, Page: 235-248
2010
  • 175
    Citations
  • 0
    Usage
  • 224
    Captures
  • 0
    Mentions
  • 0
    Social Media
Metric Options:   Counts1 Year3 Year

Metrics Details

  • Citations
    175
    • Citation Indexes
      173
    • Clinical Citations
      1
      • PubMed Guidelines
        1
    • Policy Citations
      1
      • Policy Citation
        1
  • Captures
    224

Article Description

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.

Bibliographic Details

http://www.sciencedirect.com/science/article/pii/S1535610810000371; http://dx.doi.org/10.1016/j.ccr.2009.12.046; http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=77649311945&origin=inward; http://www.ncbi.nlm.nih.gov/pubmed/20227038; https://facultyopinions.com/prime/2707957#eval2602059; http://dx.doi.org/10.3410/f.2707957.2602059; https://linkinghub.elsevier.com/retrieve/pii/S1535610810000371; https://facultyopinions.com/prime/2707957#eval2371055; http://dx.doi.org/10.3410/f.2707957.2371055; http://www.cell.com/cancer-cell/abstract/S1535-6108(10)00037-1; http://f1000.com/2707957#eval2371055; http://f1000.com/2707957#eval2602059; http://linkinghub.elsevier.com/retrieve/pii/S1535610810000371; http://europepmc.org/abstract/med/20227038; http://europepmc.org/articles/PMC2845806; https://secure.jbs.elsevierhealth.com/action/getSharedSiteSession?redirect=http%3A%2F%2Fwww.cell.com%2Fcancer-cell%2Fabstract%2FS1535-6108%2810%2900037-1&rc=0&code=cell-site; http://acw.elsevier.com/SSOCore?return=https%3A%2F%2Fsecure.jbs.elsevierhealth.com%2Faction%2FconsumeSsoCookie%3FredirectUri%3Dhttp%253A%252F%252Fwww.cell.com%252Faction%252FconsumeSharedSessionAction%253FJSESSIONID%253DaaaEbLbuCkVpX8XIV33xv%2526MAID%253DMyOsJcXrOsOly6Z7pl91Rg%25253D%25253D%2526SERVER%253DWZ6myaEXBLFhx%25252B6Ws3Nrug%25253D%25253D%2526ORIGIN%253D424372823%2526RD%253DRD; http://acw.elsevier.com/SSOCore/?return=https%3A%2F%2Fsecure.jbs.elsevierhealth.com%2Faction%2FconsumeSsoCookie%3FredirectUri%3Dhttp%253A%252F%252Fwww.cell.com%252Faction%252FconsumeSharedSessionAction%253FJSESSIONID%253DaaaEbLbuCkVpX8XIV33xv%2526MAID%253DMyOsJcXrOsOly6Z7pl91Rg%25253D%25253D%2526SERVER%253DWZ6myaEXBLFhx%25252B6Ws3Nrug%25253D%25253D%2526ORIGIN%253D424372823%2526RD%253DRD; https://secure.jbs.elsevierhealth.com/action/consumeSsoCookie?redirectUri=http%3A%2F%2Fwww.cell.com%2Faction%2FconsumeSharedSessionAction%3FJSESSIONID%3DaaaEbLbuCkVpX8XIV33xv%26MAID%3DMyOsJcXrOsOly6Z7pl91Rg%253D%253D%26SERVER%3DWZ6myaEXBLFhx%252B6Ws3Nrug%253D%253D%26ORIGIN%3D424372823%26RD%3DRD&acw=&utt=

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

Faculty Opinions Ltd

Medicine; Biochemistry, Genetics and Molecular Biology

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