Banda Douglas M, Nuñez Nicole N, Burnside Michael A, Bradshaw Katie M, David Sheila S
Department of Chemistry, University of California, Davis, One Shields Avenue, Davis, CA 95616, United States.
Department of Chemistry, University of California, Davis, One Shields Avenue, Davis, CA 95616, United States.
Free Radic Biol Med. 2017 Jun;107:202-215. doi: 10.1016/j.freeradbiomed.2017.01.008. Epub 2017 Jan 10.
Reactive oxygen and nitrogen species (RONS) may infringe on the passing of pristine genetic information by inducing DNA inter- and intra-strand crosslinks, protein-DNA crosslinks, and chemical alterations to the sugar or base moieties of DNA. 8-Oxo-7,8-dihydroguanine (8-oxoG) is one of the most prevalent DNA lesions formed by RONS and is repaired through the base excision repair (BER) pathway involving the DNA repair glycosylases OGG1 and MUTYH in eukaryotes. MUTYH removes adenine (A) from 8-oxoG:A mispairs, thus mitigating the potential of G:C to T:A transversion mutations from occurring in the genome. The paramount role of MUTYH in guarding the genome is well established in the etiology of a colorectal cancer predisposition syndrome involving variants of MUTYH, referred to as MUTYH-associated polyposis (MAP). In this review, we highlight recent advances in understanding how MUTYH structure and related function participate in the manifestation of human disease such as MAP. Here we focus on the importance of MUTYH's metal cofactor sites, including a recently discovered "Zinc linchpin" motif, as well as updates to the catalytic mechanism. Finally, we touch on the insight gleaned from studies with MAP-associated MUTYH variants and recent advances in understanding the multifaceted roles of MUTYH in the cell, both in the prevention of mutagenesis and tumorigenesis.
活性氧和氮物种（RONS）可能通过诱导DNA链间和链内交联、蛋白质-DNA交联以及对DNA糖基或碱基部分的化学改变来破坏原始遗传信息的传递。8-氧代-7,8-二氢鸟嘌呤（8-oxoG）是RONS形成的最常见的DNA损伤之一，并通过碱基切除修复（BER）途径进行修复，该途径在真核生物中涉及DNA修复糖基化酶OGG1和MUTYH。MUTYH从8-oxoG:A错配中去除腺嘌呤（A），从而降低基因组中G:C到T:A颠换突变发生的可能性。MUTYH在保护基因组中的重要作用在一种涉及MUTYH变体的结直肠癌易感性综合征（称为MUTYH相关息肉病，MAP）的病因学中已得到充分证实。在这篇综述中，我们重点介绍了在理解MUTYH结构和相关功能如何参与人类疾病（如MAP）表现方面的最新进展。在这里，我们关注MUTYH金属辅因子位点的重要性，包括最近发现的“锌关键”基序，以及催化机制的更新。最后，我们探讨了从与MAP相关的MUTYH变体研究中获得的见解，以及在理解MUTYH在细胞中预防诱变和肿瘤发生的多方面作用方面的最新进展。
