University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA.
Nat Chem. 2018 Aug;10(8):873-880. doi: 10.1038/s41557-018-0068-x. Epub 2018 Jun 18.
The human DNA repair enzyme MUTYH excises mispaired adenine residues in oxidized DNA. Homozygous MUTYH mutations underlie the autosomal, recessive cancer syndrome MUTYH-associated polyposis. We report a MUTYH variant, p.C306W (c.918C>G), with a tryptophan residue in place of native cysteine, that ligates the [4Fe4S] cluster in a patient with colonic polyposis and family history of early age colon cancer. In bacterial MutY, the [4Fe4S] cluster is redox active, allowing rapid localization to target lesions by long-range, DNA-mediated signalling. In the current study, using DNA electrochemistry, we determine that wild-type MUTYH is similarly redox-active, but MUTYH C306W undergoes rapid oxidative degradation of its cluster to [3Fe4S], with loss of redox signalling. In MUTYH C306W, oxidative cluster degradation leads to decreased DNA binding and enzyme function. This study confirms redox activity in eukaryotic DNA repair proteins and establishes MUTYH C306W as a pathogenic variant, highlighting the essential role of redox signalling by the [4Fe4S] cluster.
人类 DNA 修复酶 MUTYH 能切除氧化 DNA 中错配的腺嘌呤残基。纯合 MUTYH 突变是常染色体隐性遗传癌症综合征 MUTYH 相关息肉病的基础。我们报道了一个 MUTYH 变体，p.C306W（c.918C>G），在一个有结肠息肉病和家族性早发性结肠癌病史的患者中，天然半胱氨酸被色氨酸取代，从而连接了[4Fe4S]簇。在细菌 MutY 中，[4Fe4S]簇具有氧化还原活性，允许通过长距离、DNA 介导的信号快速定位靶损伤。在本研究中，我们使用 DNA 电化学测定法确定野生型 MUTYH 也具有类似的氧化还原活性，但 MUTYH C306W 的簇迅速氧化降解为[3Fe4S]，失去氧化还原信号。在 MUTYH C306W 中，氧化簇的降解导致 DNA 结合和酶功能下降。本研究证实了真核 DNA 修复蛋白的氧化还原活性，并将 MUTYH C306W 确定为一种致病性变体，突出了[4Fe4S]簇的氧化还原信号的重要作用。
