DNA is comprised of chemically reactive nucleobases that exist under a constant barrage from damaging agents. Failure to repair chemical modifications to these nucleobases can result in mutations that can cause various diseases, including cancer. Fortunately, the base excision repair (BER) pathway can repair modified nucleobases and prevent these deleterious mutations. However, this pathway can be hindered through several mechanisms. For instance, mutations to the enzymes in the BER pathway have been identified in cancers. Biochemical characterisation of these mutants has elucidated various mechanisms that inhibit their activity. Furthermore, the packaging of DNA into chromatin poses another obstacle to the ability of BER enzymes to function properly. Investigations of BER in the base unit of chromatin, the nucleosome core particle (NCP), have revealed that the NCP acts as a complex substrate for BER enzymes. The constituent proteins of the NCP, the histones, also have variants that can further impact the structure of the NCP and may modulate access of enzymes to the packaged DNA. These histone variants have also displayed significant clinical effects both in carcinogenesis and patient prognosis. This review focuses on the underlying molecular mechanisms that present obstacles to BER and the relationship of these obstacles to cancer. In addition, several chemotherapeutics induce DNA damage that can be repaired by the BER pathway and understanding obstacles to BER can inform how resistance and/or sensitivity to these therapies may occur. With the understanding of these molecular mechanisms, current chemotherapeutic treatment regiments may be improved, and future therapies developed.

中文翻译：

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染色质和碱基切除修复的其他障碍：在致癌作用中的潜在作用。

DNA由化学反应性核碱基组成，这些核碱基在不断受到破坏剂的干扰下一直存在。无法修复对这些核碱基的化学修饰会导致突变，导致多种疾病，包括癌症。幸运的是，碱基切除修复（BER）途径可以修复修饰的核碱基并防止这些有害突变。但是，可以通过几种机制来阻止此途径。例如，在癌症中已经确定了BER途径中酶的突变。这些突变体的生化特性阐明了抑制其活性的各种机制。此外，将DNA包装到染色质中对BER酶正确发挥功能的能力构成了另一个障碍。研究染色质基本单元，核小体核心颗粒（NCP）中的BER 已经表明，NCP充当BER酶的复杂底物。NCP的组成蛋白，即组蛋白，也具有可以进一步影响NCP结构并可以调节酶进入包装DNA的变异体。这些组蛋白变体在致癌和患者预后方面也显示出显着的临床效果。这篇综述着重介绍了潜在的分子机制，这些机制提出了BER障碍以及这些障碍与癌症之间的关系。此外，几种化学治疗剂可诱导DNA损伤，可通过BER途径修复该损伤，了解BER的障碍可告知可能如何发生对这些疗法的耐药性和/或敏感性。通过了解这些分子机制，可以改善当前的化学治疗方案，并开发出未来的疗法。