Oxidized bases in the genome has been implicated in various human pathologies, including cancer, aging and neurological diseases. Their repair is initiated with excision by DNA glycosylases (DGs) in the base excision repair (BER) pathway. Among the five oxidized base-specific human DGs, OGG1 and NTH1 preferentially excise oxidized purines and pyrimidines, respectively, while NEILs remove both oxidized purines and pyrimidines. However, little is known about why cells possess multiple DGs with overlapping substrate specificities. Studies of the past decades revealed that some DGs are involved in repair of oxidized DNA base lesions in the actively transcribed regions. Preferential removal of lesions from the transcribed strands of active genes, called transcription-coupled repair (TCR), was discovered as a distinct sub-pathway of nucleotide excision repair; however, such repair of oxidized DNA bases had not been established until our recent demonstration of NEIL2’s role in TC-BER of the nuclear genome. We have shown that NEIL2 forms a distinct transcriptionally active, repair proficient complex. More importantly, we for the first time reconstituted TC-BER using purified components. These studies are important for characterizing critical requirement for the process. However, because NEIL2 cannot remove all types of oxidized bases, it is unlikely to be the only DNA glycosylase involved in TC-BER. Hence, we postulate TC-BER process to be universally involved in maintaining the functional integrity of active genes, especially in post-mitotic, non-growing cells. We further postulate that abnormal bases (e.g., uracil), and alkylated and other small DNA base adducts are also repaired via TC-BER. In this review, we have provided an overview of the various aspects of TC-BER in mammalian cells with the hope of generating significant interest of many researchers in the field. Further studies aimed at better understanding the mechanistic aspects of TC-BER could help elucidate the linkage of TC-BER deficiency to various human pathologies.

基因组中的氧化碱基与多种人类病理有关，包括癌症、衰老和神经系统疾病。它们的修复是通过碱基切除修复 (BER) 途径中 DNA 糖基化酶 (DG) 的切除启动的。在五种氧化碱基特异性人类 DG 中，OGG1 和 NTH1 分别优先切除氧化嘌呤和嘧啶，而 NEIL 则同时去除氧化嘌呤和嘧啶。然而，对于细胞为何拥有多个具有重叠底物特异性的 DG，人们知之甚少。过去几十年的研究表明，一些 DG 参与活跃转录区域氧化 DNA 碱基损伤的修复。优先去除活性基因转录链中的病变，称为转录偶联修复（TCR），被发现是核苷酸切除修复的一个独特的子途径。然而，直到我们最近证明了 NEIL2 在核基因组 TC-BER 中的作用，这种氧化 DNA 碱基的修复才得以建立。我们已经证明 NEIL2 形成了一种独特的转录活性、修复能力强的复合物。更重要的是，我们首次使用纯化的组件重构了 TC-BER。这些研究对于描述过程的关键要求非常重要。然而，由于 NEIL2 无法去除所有类型的氧化碱基，因此它不太可能是参与 TC-BER 的唯一 DNA 糖基化酶。因此，我们假设 TC-BER 过程普遍参与维持活性基因的功能完整性，特别是在有丝分裂后的非生长细胞中。我们进一步假设异常碱基（例如尿嘧啶）以及烷基化和其他小 DNA 碱基加合物也可以通过TC-BER 进行修复。 在这篇综述中，我们概述了哺乳动物细胞中 TC-BER 的各个方面，希望引起该领域许多研究人员的浓厚兴趣。旨在更好地了解 TC-BER 机制的进一步研究可能有助于阐明 TC-BER 缺陷与各种人类病理的联系。