Tam Annie S, Chu Jeffrey S C, Rose Ann M
Department of Medical Genetics, University of British Columbia, Vancouver, V6T 1Z3, Canada Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, V5Z 1L3, Canada
WuHan Frasergen Bioinformatics Co. Ltd., Wuhan, Hubei Province, 430075, China.
G3 (Bethesda). 2015 Nov 12;6(1):133-40. doi: 10.1534/g3.115.021915.
Cancer therapy largely depends on chemotherapeutic agents that generate DNA lesions. However, our understanding of the nature of the resulting lesions as well as the mutational profiles of these chemotherapeutic agents is limited. Among these lesions, DNA interstrand crosslinks are among the more toxic types of DNA damage. Here, we have characterized the mutational spectrum of the commonly used DNA interstrand crosslinking agent mitomycin C (MMC). Using a combination of genetic mapping, whole genome sequencing, and genomic analysis, we have identified and confirmed several genomic lesions linked to MMC-induced DNA damage in Caenorhabditis elegans. Our data indicate that MMC predominantly causes deletions, with a 5'-CpG-3' sequence context prevalent in the deleted regions of DNA. Furthermore, we identified microhomology flanking the deletion junctions, indicative of DNA repair via nonhomologous end joining. Based on these results, we propose a general repair mechanism that is likely to be involved in the biological response to this highly toxic agent. In conclusion, the systematic study we have described provides insight into potential sequence specificity of MMC with DNA.
癌症治疗在很大程度上依赖于能产生DNA损伤的化疗药物。然而，我们对由此产生的损伤的性质以及这些化疗药物的突变谱的了解是有限的。在这些损伤中，DNA链间交联是毒性更强的DNA损伤类型之一。在此，我们对常用的DNA链间交联剂丝裂霉素C（MMC）的突变谱进行了表征。通过结合遗传定位、全基因组测序和基因组分析，我们在秀丽隐杆线虫中鉴定并确认了几种与MMC诱导的DNA损伤相关的基因组损伤。我们的数据表明，MMC主要导致缺失，在DNA的缺失区域中5'-CpG-3'序列背景普遍存在。此外，我们在缺失连接处两侧鉴定出微同源性，这表明通过非同源末端连接进行DNA修复。基于这些结果，我们提出了一种可能参与对这种高毒性药物的生物学反应的一般修复机制。总之，我们所描述的系统研究为MMC与DNA潜在的序列特异性提供了见解。
