Not breathing is not an option: How to deal with oxidative DNA damage

These results demonstrated that only Pol λ was able to assist Pol δ to selectively perform the correct insertion of C opposite 8-oxo-G by enhancing exclusively the correct bypass of 8-oxo-G using C, while Pols β and η lacked selectivity and even preferentially enhanced erroneous bypass of 8-oxo-G

Enni Markkanen


Scholarcy highlights

  • Oxidative DNA damage constitutes a major threat to genetic integrity, and has been implicated in the pathogenesis of a wide variety of diseases, including cancer and neurodegeneration. 7,8dihydro-8oxo-deoxyGuanine is one of the best characterised oxidative DNA lesions, and it can give rise to point mutations due to its miscoding potential that instructs most DNA polymerases to preferentially insert Adenine opposite 8-oxo-G instead of the correct Cytosine
  • While oxidative DNA damage was shown to be completely repaired in the rest of the genome, it was found to persist in telomeric regions of human primary fibroblasts, and to induce significant temporary telomere shortening as well as increased chromosomal instability within 48 h after oxidative stress, which was restored to almost normal values subsequently. These results suggested a correlation between oxidative DNA damage, telomere length, and abnormal nuclear morphologies induced by chromosome instability
  • The mechanisms underlying its repair are being progressively unveiled in detail owing to extensive efforts by a large number of contributing investigators
  • While the basic framework built of understanding the underlying biochemical reactions and interactions of the different players is very solid, much still needs to be done to fill in the more complicated or perhaps just less explored details that are essential for an integrated comprehension of the cellular systems that lead to safekeeping of the genome
  • But are certainly not limited to: where exactly does oxidative DNA damage accumulate? How are different aspects of its repair regulated in the context of the cell cycle, especially during S-phase? How do these welldefined repair pathways perform in the context chromatin? What influence does chromatin remodelling have on these reactions? How is the interplay between the various different and sometimes overlapping repair activities managed? What are there more profound tissue- and cell-type specific differences in these mechanisms that underlie the differences in disease predisposition? Unravelling these riddles will necessitate considerable efforts, but is expected to yield important insights to further clarify the connection between oxidative DNA damage, its repair and human diseases
  • By using a multivariate logistic regression analysis, low expression of X-ray repair cross-complementing protein 1 was significantly associated with an increased risk for both squamous intraepithelial lesions and carcinoma of the cervix
  • Considering the clear involvement of oxidative DNA damage repair in the onset and pathogenesis of many different human pathologies, more detailed understanding of these mechanisms in the context of the organism might well pave the way for successful preventive and therapeutic approaches involving the repair of oxidatively damaged DNA

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