文章：

DNA链间交联修复与癌症

DNA interstrand crosslink repair and cancer

原文发布日期：2011-06-24

DOI: 10.1038/nrc3088

类型: Review Article

开放获取: 否

要点：

1. DNA interstrand crosslinks (ICLs) may arise following exposure to environmental mutagens, and are potently toxic when induced in large numbers by chemotherapeutic drugs. ICL-based chemotherapy is one of the most widely used forms of cancer treatment, particularly in the treatment of leukaemias.
2. Fanconi anaemia (FA) is a disorder that results in sensitivity to ICLs, which is caused by the mutation of one of at least 14 different genes. Although their functions have not been completely elucidated, there is substantial evidence to suggest that these genes, including the BRCA2 (also known as FANCD1) breast and ovarian cancer tumour suppressor, participate in a common pathway of ICL repair.
3. Homologous recombination (HR)-mediated repair of ICLs is promoted by the FA pathway. FA cells that are exposed to ICL-inducing agents, or chronically treated wild-type cells, may use alternative pathways of repair that lead to deleterious genetic aberrations such as radial chromosomes.
4. Structure-specific nucleases and translesion polymerases participate in the coordinated removal of the ICL and the resumption or completion of DNA replication. There is increasing evidence that non-replication-associated repair of ICLs also takes place — however, this is insufficient to remove all ICL damage.
5. The modulation of ICL repair could improve chemotherapy outcomes. For example, the dose-limiting toxicities of ICLs mostly affect the blood system, so increasing the ability to repair ICLs in blood cells could prevent anaemia phenotypes. Alternatively, targeted downregulation of ICL repair in tumours could improve ICL-mediated tumour killing.

要点翻译：

1. DNA链间交联可由环境诱变剂引发，当化疗药物诱导产生大量交联时会产生强烈毒性。基于链间交联的化疗是应用最广泛的癌症治疗手段之一，尤其在白血病治疗领域。
2. 范可尼贫血症是一种导致对链间交联敏感的遗传性疾病，由至少14个不同基因中的任一突变引起。尽管这些基因的功能尚未完全阐明，但有充分证据表明它们（包括BRCA2乳腺癌卵巢癌抑癌基因，亦称为FANCD1）共同参与了链间交联修复通路。
3. 范可尼贫血通路促进同源重组介导的链间交联修复。暴露于链间交联诱导剂的范可尼贫血细胞，或长期处理的野生型细胞，可能采用其他修复途径导致有害遗传异常（如放射状染色体）。
4. 结构特异性核酸酶和跨损伤聚合酶协同参与链间交联的清除及DNA复制的重启或完成。越来越多证据表明，非复制相关的链间交联修复同样存在，但该机制不足以清除所有链间交联损伤。
5. 调控链间交联修复可改善化疗效果。例如：链间交联的剂量限制性毒性主要影响血液系统，因此增强血细胞修复链间交联的能力可预防贫血表型；反之，在肿瘤中有靶向下调链间交联修复能力，可增强链间交联介导的肿瘤杀伤效果。

英文摘要：

Interstrand crosslinks (ICLs) are highly toxic DNA lesions that prevent transcription and replication by inhibiting DNA strand separation. Agents that induce ICLs were one of the earliest, and are still the most widely used, forms of chemotherapeutic drug. Only recently, however, have we begun to understand how cells repair these lesions. Important insights have come from studies of individuals with Fanconi anaemia (FA), a rare genetic disorder that leads to ICL sensitivity. Understanding how the FA pathway links nucleases, helicases and other DNA-processing enzymes should lead to more targeted uses of ICL-inducing agents in cancer treatment and could provide novel insights into drug resistance.

摘要翻译： 

链间交联（ICL）是极具毒性的DNA损伤，通过抑制DNA链分离来阻断转录和复制。诱导ICL的药物是最早出现、至今仍在广泛应用的化疗药物之一。然而，直到最近，我们才开始理解细胞如何修复这些损伤。对范可尼贫血（FA）患者的研究提供了重要启示，这是一种导致ICL敏感性的罕见遗传病。阐明FA通路如何连接核酸酶、解旋酶及其他DNA加工酶，将有助于更精准地将ICL诱导剂用于癌症治疗，并可能为耐药机制提供新见解。

原文链接：

DNA interstrand crosslink repair and cancer