Cisplatin DNA damage and repair maps of the human genome at single-nucleotide resolution
Cisplatin DNA damage and repair maps of the human genome at single-nucleotide resolution
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DOI：
10.1073/pnas.1614430113
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发表时间：
2016-10-11
影响因子：
11.1
通讯作者：
Adar, Sheera
中科院分区：
文献类型：
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作者：
Hu, Jinchuan;Lieb, Jason D.;Adar, Sheera
顺铂是一种主要的抗癌药物，通过破坏癌细胞的DNA来杀死癌细胞。癌细胞通过核苷酸切除修复来清除损伤，从而科普药物。我们已经开发了方法来测量顺铂加合物的形成和它的修复在单核苷酸分辨率。“Damage-seq”依赖于巨大基底病变的复制阻断特性来精确绘制其位置。“XR-seq”通过捕获和测序在修复期间释放的切除的寡聚体来独立地映射这些损伤的去除。我们生成的损伤和修复图显示，损伤分布基本上是均匀的，主要由潜在的序列决定。相比之下，顺铂修复在基因组中是异质性的，并且受到包括转录和染色质状态在内的多种因素的影响。因此，基因组中损伤的总体效应主要不是由损伤形成而是由修复效率驱动的。Damage-seq和XR-seq方法的组合具有开发新型癌症治疗策略的潜力。
Cisplatin is a major anticancer drug that kills cancer cells by damaging their DNA. Cancer cells cope with the drug by removal of the damages with nucleotide excision repair. We have developed methods to measure cisplatin adduct formation and its repair at single-nucleotide resolution. "Damage-seq" relies on the replication-blocking properties of the bulky base lesions to precisely map their location. "XR-seq" independently maps the removal of these damages by capturing and sequencing the excised oligomer released during repair. The damage and repair maps we generated reveal that damage distribution is essentially uniform and is dictated mostly by the underlying sequence. In contrast, cisplatin repair is heterogeneous in the genome and is affected by multiple factors including transcription and chromatin states. Thus, the overall effect of damages in the genome is primarily driven not by damage formation but by the repair efficiency. The combination of the Damage-seq and XR-seq methods has the potential for developing novel cancer therapeutic strategies.