Burgos-Morón Estefanía, Calderón-Montaño José Manuel, Pastor Nuria, Höglund Andreas, Ruiz-Castizo Ángel, Domínguez Inmaculada, López-Lázaro Miguel, Hajji Nabil, Helleday Thomas, Mateos Santiago, Orta Manuel Luis
Department of Pharmacology, Faculty of Pharmacy, University of Seville, 41012 Seville, Spain.
Department of Cell Biology, Faculty of Biology, University of Seville, 41012 Seville, Spain.
Oncotarget. 2018 Oct 12;9(80):35069-35084. doi: 10.18632/oncotarget.26189.
The Cockayne Syndrome Protein B (CSB) plays an essential role in Transcription-Coupled Nucleotide Excision Repair (TC-NER) by recruiting repair proteins once transcription is blocked with a DNA lesion. In fact, CSB-deficient cells are unable to recover from transcription-blocking DNA lesions. 5-Aza-2'-deoxycytidine (5-azadC) is a nucleoside analogue that covalently traps DNA methyltransferases (DNMTs) onto DNA. This anticancer drug has a double mechanism of action: it reverts aberrant hypermethylation in tumour-suppressor genes, and it induces DNA damage. We have recently reported that Homologous Recombination and XRCC1/PARP play an important role in the repair of 5-azadC-induced DNA damage. However, the mechanisms involved in the repair of the DNMT adducts induced by azadC remain poorly understood. In this paper, we show for the first time the importance of CSB in the repair of azadC-induced DNA lesions. We propose a model in which CSB initiates a signalling pathway to repair transcription blocks induced by incorporated 5-azadC. Indeed, CSB-deficient cells treated with 5-azadC show a delay in the repair of trapped DNMT1, increased levels of DNA damage and reduced survival.
科凯恩综合征蛋白B（CSB）在转录偶联核苷酸切除修复（TC-NER）中发挥着至关重要的作用，它能在转录因DNA损伤而受阻时招募修复蛋白。事实上，缺乏CSB的细胞无法从转录阻断性DNA损伤中恢复。5-氮杂-2'-脱氧胞苷（5-azadC）是一种核苷类似物，它能将DNA甲基转移酶（DNMTs）共价捕获到DNA上。这种抗癌药物具有双重作用机制：它能逆转肿瘤抑制基因中的异常高甲基化，还能诱导DNA损伤。我们最近报道，同源重组和XRCC1/PARP在5-azadC诱导的DNA损伤修复中发挥重要作用。然而，关于azadC诱导的DNMT加合物的修复机制仍知之甚少。在本文中，我们首次展示了CSB在azadC诱导的DNA损伤修复中的重要性。我们提出了一个模型，其中CSB启动一条信号通路来修复由掺入的5-azadC诱导的转录阻断。的确，用5-azadC处理的CSB缺陷细胞在捕获的DNMT1修复方面出现延迟，DNA损伤水平增加，存活率降低。
