106 It may be that at the expense of generating mutations, mammalian cells may use transient up-regulation of Pol ι to deal with replication arrest by DNA damage for survival.107 However, continuous over-expression of such error prone DNA polymerase, for instance by chronic hypoxia, may

result in a high rate of point mutations.108 As mentioned above, germline mutations in NBS1 predispose it to the Nijmegen breakage syndrome. The NBS1 protein forms a complex with MRE11A and RAD50 called MRN, which interacts with double-strand breaks and begins the DNA damage response by recruiting the ATM protein (see above). Inactivation of NBS1 impairs the function of MRN, leading to a high sensitivity to radiation, CIN and defective cell cycle checkpoints. To et al. demonstrated that hypoxia (1% O2 for Romidepsin solubility dmso 16 h) down-regulates NBS1 expression at the mRNA and protein levels in cancer cell lines.109 They showed that this down-regulation is

HIF1 but not HIF2 dependent and is mediated by reduction of Sp1-MYC by competing Sp1-HIF1 at the promoter region of the NBS1 locus, similar to the MSH2 locus.86,109 All cancers contain a much greater number of genetic and epigenetic alterations than do corresponding PLX3397 normal cells. At nucleotide levels, these alterations include: substitutions of one base by another,

insertions or deletions of small or large segments of DNA, rearrangements, copy number increases, copy number reductions, acquisition of foreign DNA (virus) in some cases and hypermethylation Atorvastatin or hypomethylation of guanosine residue.3 The cancer genome also shows changes in numbers of whole or parts of chromosomes. It is reasonable to assume that these genetic alterations can be caused in part by exposure to environmental carcinogens. Data from the whole genome sequencing of melanoma showed clearly the contribution of UV radiation to the melanoma genome.110 Interestingly, there is a sign of the second genetic insult after UV damage is detected in the genome and this is characterized by an increase in the frequency of C > A transversions.110 It is tempting to speculate that the second event occurring in the melanoma genome may be associated with H/R. As reviewed in this article, H/R is a strong candidate for induction of genetic alterations and the DNA damage response found in cancer genomes and tissues; however, our insights into H/R on the cellular genome are all based on experiments performed in tissue culture or in animal models. The question is whether H/R really plays the same contributing role for genetic instability in human tumor tissues as observed in experimental systems.