Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA.
Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
Int J Mol Sci. 2023 Sep 16;24(18):14186. doi: 10.3390/ijms241814186.
Base excision repair (BER) corrects forms of oxidative, deamination, alkylation, and abasic single-base damage that appear to have minimal effects on the helix. Since its discovery in 1974, the field has grown in several facets: mechanisms, biology and physiology, understanding deficiencies and human disease, and using BER genes as potential inhibitory targets to develop therapeutics. Within its segregation of short nucleotide (SN-) and long patch (LP-), there are currently six known global mechanisms, with emerging work in transcription- and replication-associated BER. Knockouts (KOs) of BER genes in mouse models showed that single glycosylase knockout had minimal phenotypic impact, but the effects were clearly seen in double knockouts. However, KOs of downstream enzymes showed critical impact on the health and survival of mice. BER gene deficiency contributes to cancer, inflammation, aging, and neurodegenerative disorders. Medicinal targets are being developed for single or combinatorial therapies, but only PARP and APE1 have yet to reach the clinical stage.
碱基切除修复 (BER) 可纠正氧化、脱氨、烷基化和无碱基单碱基损伤等形式的损伤，这些损伤似乎对螺旋结构的影响最小。自 1974 年发现以来，该领域在多个方面得到了发展：机制、生物学和生理学、理解缺陷和人类疾病，以及将 BER 基因用作潜在的抑制靶点来开发治疗方法。在短核苷酸 (SN-) 和长补丁 (LP-) 的分离中，目前有六种已知的全局机制，在转录和复制相关的 BER 中也有新的工作。在小鼠模型中敲除 BER 基因的 KO 实验表明，单个糖苷酶的 KO 对表型几乎没有影响，但在双 KO 中则明显可见。然而，下游酶的 KO 对小鼠的健康和生存产生了至关重要的影响。BER 基因的缺失会导致癌症、炎症、衰老和神经退行性疾病。正在开发针对单一或组合疗法的药物靶点，但只有 PARP 和 APE1 尚未进入临床阶段。
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