首页    期刊浏览 2024年11月08日 星期五
登录注册

文章基本信息

  • 标题:Extracellular NAD enhances PARP-dependent DNA repair capacity independently of CD73 activity
  • 本地全文:下载
  • 作者:Anna Wilk ; Faisal Hayat ; Richard Cunningham
  • 期刊名称:Scientific Reports
  • 电子版ISSN:2045-2322
  • 出版年度:2020
  • 卷号:10
  • 期号:1
  • 页码:1-21
  • DOI:10.1038/s41598-020-57506-9
  • 出版社:Springer Nature
  • 摘要:Changes in nicotinamide adenine dinucleotide (NAD ) levels that compromise mitochondrial function trigger release of DNA damaging reactive oxygen species. NAD levels also affect DNA repair capacity as NAD is a substrate for PARP-enzymes (mono/poly-ADP-ribosylation) and sirtuins (deacetylation). The ecto-5'-nucleotidase CD73, an ectoenzyme highly expressed in cancer, is suggested to regulate intracellular NAD levels by processing NAD and its bio-precursor, nicotinamide mononucleotide (NMN), from tumor microenvironments, thereby enhancing tumor DNA repair capacity and chemotherapy resistance. We therefore investigated whether expression of CD73 impacts intracellular NAD content and NAD -dependent DNA repair capacity. Reduced intracellular NAD levels suppressed recruitment of the DNA repair protein XRCC1 to sites of genomic DNA damage and impacted the amount of accumulated DNA damage. Further, decreased NAD reduced the capacity to repair DNA damage induced by DNA alkylating agents. Overall, reversal of these outcomes through NAD or NMN supplementation was independent of CD73. In opposition to its proposed role in extracellular NAD bioprocessing, we found that recombinant human CD73 only poorly processes NMN but not NAD . A positive correlation between CD73 expression and intracellular NAD content could not be made as CD73 knockout human cells were efficient in generating intracellular NAD when supplemented with NAD or NMN.
国家哲学社会科学文献中心版权所有