The contribution of DNA base damage to human cancer is modulated by the base excision repair interaction network.
ABSTRACT Base excision repair (BER) is a major mode of repair of DNA base damage. BER is required for maintenance of genetic stability, which is important in the prevention of cancer. However, direct genetic associations between BER deficiency and human cancer have been difficult to firmly establish, and the first-generation mouse models deficient in individual DNA-glycosylases, which are the enzymes that give lesion specificity to the BER pathway, generally do not develop spontaneous tumors. This review summarizes our current understanding of the contribution of DNA base damage to human cancer, with a particular focus on DNA-glycosylases and two of the main enzymes that prevent misincorporation of damaged deoxynucleotide triphosphates into DNA: the dUTPase and MTH1. The available evidence suggests that the most important factors determining individual susceptibility to cancer are not mutations in individual DNA repair enzymes but rather the regulation of expression and modulation of function by protein modification and interaction partners. With this in mind, we present a comprehensive list of protein-protein interactions involving DNA-glycosylases or either of the two enzymes that limit incorporation of damaged nucleotides into DNA. Interacting partners with a known role in human cancer are specifically highlighted.
- SourceAvailable from: Oyvind Fensgard[show abstract] [hide abstract]
ABSTRACT: Activation of oxidative stress-responses and downregulation of insulin-like signaling (ILS) is seen in Nucleotide Excision Repair (NER) deficient segmental progeroid mice. Evidence suggests that this is a survival response to persistent transcription-blocking DNA damage, although the relevant lesions have not been identified. Here we show that loss of NTH-1, the only Base Excision Repair (BER) enzyme known to initiate repair of oxidative DNA damage inC. elegans, restores normal lifespan of the short-lived NER deficient xpa-1 mutant. Loss of NTH-1 leads to oxidative stress and global expression profile changes that involve upregulation of genes responding to endogenous stress and downregulation of ILS. A similar, but more extensive, transcriptomic shift is observed in the xpa-1 mutant whereas loss of both NTH-1 and XPA-1 elicits a different profile with downregulation of Aurora-B and Polo-like kinase 1 signaling networks as well as DNA repair and DNA damage response genes. The restoration of normal lifespan and absence oxidative stress responses in nth-1;xpa-1 indicate that BER contributes to generate transcription blocking lesions from oxidative DNA damage. Hence, our data strongly suggests that the DNA lesions relevant for aging are repair intermediates resulting from aberrant or attempted processing by BER of lesions normally repaired by NER.Aging 03/2010; 2(3):133-59. · 4.70 Impact Factor