Circadian control of XPA and excision repair of cisplatin-DNA damage by cryptochrome and HERC2 ubiquitin ligase
Circadian control of XPA and excision repair of cisplatin-DNA damage by cryptochrome and HERC2 ubiquitin ligase
复制标题
DOI：
10.1073/pnas.0915085107
复制
发表时间：
2010-03-16
影响因子：
11.1
通讯作者：
Sancar, Aziz
中科院分区：
文献类型：
--
作者：
Kang, Tae-Hong;Lindsey-Boltz, Laura A.;Sancar, Aziz
顺铂是最常用的抗癌药物之一。它通过破坏癌细胞的DNA来杀死癌细胞，因此细胞DNA修复能力是其疗效的重要决定因素。在这里，我们研究了顺铂诱导的小鼠肝脏和睾丸组织提取物中DNA损伤的修复，这些提取物在一天的过程中定期制备。我们发现，XPA蛋白，这在修复顺铂损伤的核苷酸切除修复中起着至关重要的作用，表现出昼夜节律振荡，在肝脏，但不是在睾丸。因此，去除肝脏提取物中的顺铂加合物，而不是睾丸提取物中的顺铂加合物，表现出昼夜节律模式，顶点在下午5点附近，最低点在凌晨5点附近。此外，我们发现XPA的昼夜节律振荡是通过调节核心生物钟蛋白（包括隐花色素）的转录和HERC2泛素连接酶在翻译后水平的调节来实现的。这些结果可作为顺铂化疗的时机的指导。
Cisplatin is one of the most commonly used anticancer drugs. It kills cancer cells by damaging their DNA, and hence cellular DNA repair capacity is an important determinant of its efficacy. Here, we investigated the repair of cisplatin-induced DNA damage in mouse liver and testis tissue extracts prepared at regular intervals over the course of a day. We find that the XPA protein, which plays an essential role in repair of cisplatin damage by nucleotide excision repair, exhibits circadian oscillation in the liver but not in testis. Consequently, removal of cisplatin adducts in liver extracts, but not in testis extracts, exhibits a circadian pattern with zenith at similar to 5 pm and nadir at similar to 5 am. Furthermore, we find that the circadian oscillation of XPA is achieved both by regulation of transcription by the core circadian clock proteins including cryptochrome and by regulation at the posttranslational level by the HERC2 ubiquitin ligase. These findings may be used as a guide for timing of cisplatin chemotherapy.