Department of Microbiology, University of Oslo, Oslo University Hospital, Rikshospitalet, PO Box 4950 Nydalen, N-0424, Oslo, Norway.
Centre of Environmental Radioactivity (CERAD CoE), Norway and Department of Molecular Biology, Norwegian Institute of Public Health, Oslo, Norway.
Sci Rep. 2017 Jun 29;7(1):4384. doi: 10.1038/s41598-017-04472-4.
Base excision repair (BER) is a major pathway for removal of DNA base lesions and maintenance of genomic stability, which is essential in cancer prevention. DNA glycosylases recognize and remove specific lesions in the first step of BER. The existence of a number of these enzymes with overlapping substrate specificities has been thought to be the reason why single knock-out models of individual DNA glycosylases are not cancer prone. In this work we have characterized DNA glycosylases NEIL1 and NEIL2 (Neil1 /Neil2 ) double and NEIL1, NEIL2 and NEIL3 (Neil1 /Neil2 /Neil3 ) triple knock-out mouse models. Unexpectedly, our results show that these mice are not prone to cancer and have no elevated mutation frequencies under normal physiological conditions. Moreover, telomere length is not affected and there was no accumulation of oxidative DNA damage compared to wild-type mice. These results strengthen the hypothesis that the NEIL enzymes are not simply back-up enzymes for each other but enzymes that have distinct functions beyond canonical repair.
碱基切除修复 (BER) 是清除 DNA 碱基损伤和维持基因组稳定性的主要途径，这对于预防癌症至关重要。DNA 糖苷酶在 BER 的第一步中识别并去除特定的损伤。由于存在许多具有重叠底物特异性的这些酶，因此人们认为单个 DNA 糖苷酶的单一敲除模型不易患癌症。在这项工作中，我们对 NEIL1 和 NEIL2（Neil1 / Neil2）双敲除和 NEIL1、NEIL2 和 NEIL3（Neil1 / Neil2 / Neil3）三重敲除的小鼠模型进行了表征。出乎意料的是，我们的结果表明，这些小鼠不易患癌症，在正常生理条件下没有升高的突变频率。此外，与野生型小鼠相比，端粒长度不受影响，氧化 DNA 损伤也没有积累。这些结果进一步证实了 NEIL 酶不是彼此的备用酶，而是具有除了经典修复以外的独特功能的酶的假设。
