Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Biological Sciences, Vanderbilt University, Nashville, TN 37232, USA.
Cell. 2019 Jan 10;176(1-2):144-153.e13. doi: 10.1016/j.cell.2018.10.055. Epub 2018 Dec 13.
Abasic sites are one of the most common DNA lesions. All known abasic site repair mechanisms operate only when the damage is in double-stranded DNA. Here, we report the discovery of 5-hydroxymethylcytosine (5hmC) binding, ESC-specific (HMCES) as a sensor of abasic sites in single-stranded DNA. HMCES acts at replication forks, binds PCNA and single-stranded DNA, and generates a DNA-protein crosslink to shield abasic sites from error-prone processing. This unusual HMCES DNA-protein crosslink intermediate is resolved by proteasome-mediated degradation. Acting as a suicide enzyme, HMCES prevents translesion DNA synthesis and the action of endonucleases that would otherwise generate mutations and double-strand breaks. HMCES is evolutionarily conserved in all domains of life, and its biochemical properties are shared with its E. coli ortholog. Thus, HMCES is an ancient DNA lesion recognition protein that preserves genome integrity by promoting error-free repair of abasic sites in single-stranded DNA.
堿基位点是最常见的 DNA 损伤之一。所有已知的堿基位点修复机制仅在双链 DNA 中发生损伤时才起作用。在这里，我们报告了发现 5-羟甲基胞嘧啶（5hmC）结合物、ESC 特异性（HMCES）作为单链 DNA 中堿基位点的传感器。HMCES 在复制叉处起作用，与 PCNA 和单链 DNA 结合，并形成 DNA-蛋白质交联，以防止堿基位点易出错的加工。这种不寻常的 HMCES DNA-蛋白质交联中间体通过蛋白酶体介导的降解来解决。作为自杀酶，HMCES 可防止跨损伤 DNA 合成和内切酶的作用，否则会导致突变和双链断裂。HMCES 在所有生命领域中都具有进化保守性，其生化特性与其大肠杆菌同源物共享。因此，HMCES 是一种古老的 DNA 损伤识别蛋白，通过促进单链 DNA 中堿基位点的无错误修复来保护基因组完整性。
