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可切除氧化DNA中错配的腺嘌呤残基。纯合型MUTYH突变是常染色体隐性癌症综合征MUTYH相关性息肉病的基础。我们报告了一个MUTYH变体，p.C306W（c.918C> G），其中一个色氨酸残基代替了天然的半胱氨酸，该残基与结肠息肉病和早期结肠癌家族史患者的[4Fe4S]簇连接。在细菌MutY中，[4Fe4S]簇具有氧化还原活性，可以通过DNA介导的远程信号迅速定位到靶标病变。在当前的研究中，我们使用DNA电化学方法确定了野生型MUTYH具有类似的氧化还原活性，但是MUTYH C306W的簇快速经历了氧化降解，变成了[3Fe4S] ⁺，氧化还原信号丢失。在MUTYH C306W中，氧化簇降解导致DNA结合和酶功能下降。这项研究证实了真核DNA修复蛋白中的氧化还原活性，并将MUTYH C306W建立为致病性变异体，强调了[4Fe4S]簇对氧化还原信号的重要作用。