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Tdp1 处理铬酸盐诱导的单链 DNA 断裂，这些断裂会使复制叉崩溃。

Tdp1 processes chromate-induced single-strand DNA breaks that collapse replication forks.

机构信息

Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, United States of America.

National Institute of Biological Sciences, Beijing, People's Republic of China.

出版信息

PLoS Genet. 2018 Aug 27;14(8):e1007595. doi: 10.1371/journal.pgen.1007595. eCollection 2018 Aug.

DOI:10.1371/journal.pgen.1007595
PMID:30148840
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6128646/
Abstract

Hexavalent chromium [Cr(VI)] damages DNA and causes cancer, but it is unclear which DNA damage responses (DDRs) most critically protect cells from chromate toxicity. Here, genome-wide quantitative functional profiling, DDR measurements and genetic interaction assays in Schizosaccharomyces pombe reveal a chromate toxicogenomic profile that closely resembles the cancer chemotherapeutic drug camptothecin (CPT), which traps Topoisomerase 1 (Top1)-DNA covalent complex (Top1cc) at the 3' end of single-stand breaks (SSBs), resulting in replication fork collapse. ATR/Rad3-dependent checkpoints that detect stalled and collapsed replication forks are crucial in Cr(VI)-treated cells, as is Mus81-dependent sister chromatid recombination (SCR) that repairs single-ended double-strand breaks (seDSBs) at broken replication forks. Surprisingly, chromate resistance does not require base excision repair (BER) or interstrand crosslink (ICL) repair, nor does co-elimination of XPA-dependent nucleotide excision repair (NER) and Rad18-mediated post-replication repair (PRR) confer chromate sensitivity in fission yeast. However, co-elimination of Tdp1 tyrosyl-DNA phosphodiesterase and Rad16-Swi10 (XPF-ERCC1) NER endonuclease synergistically enhances chromate toxicity in top1Δ cells. Pnk1 polynucleotide kinase phosphatase (PNKP), which restores 3'-hydroxyl ends to SSBs processed by Tdp1, is also critical for chromate resistance. Loss of Tdp1 ameliorates pnk1Δ chromate sensitivity while enhancing the requirement for Mus81. Thus, Tdp1 and PNKP, which prevent neurodegeneration in humans, repair an important class of Cr-induced SSBs that collapse replication forks.

摘要

六价铬（Cr(VI)）会损害 DNA 并导致癌症，但目前尚不清楚哪种 DNA 损伤反应（DDR）能最有效地保护细胞免受铬酸盐毒性的影响。在这里，通过全基因组定量功能谱分析、DDR 测量和遗传相互作用测定，在裂殖酵母中揭示了一种与癌症化疗药物喜树碱（CPT）非常相似的铬毒性基因组图谱，CPT 会在单链断裂（SSB）的 3'端捕获拓扑异构酶 1（Top1）-DNA 共价复合物（Top1cc），导致复制叉崩溃。ATR/Rad3 依赖性检查点在检测停滞和崩溃的复制叉方面对于 Cr(VI)处理的细胞至关重要，就像 Mus81 依赖性姐妹染色单体重组（SCR）一样，它可以修复在断裂的复制叉处的单端双链断裂（seDSB）。令人惊讶的是，铬酸盐抗性并不需要碱基切除修复（BER）或链间交联（ICL）修复，也不需要消除 XPA 依赖性核苷酸切除修复（NER）和 Rad18 介导的复制后修复（PRR），就可以使裂殖酵母对铬酸盐敏感。然而，消除 Tdp1 酪氨酸-DNA 磷酸二酯酶和 Rad16-Swi10（XPF-ERCC1）NER 内切酶协同增强了 top1Δ细胞中铬酸盐的毒性。多核苷酸激酶磷酸酶（PNKP）可以将 Tdp1 处理过的 SSB 的 3'-羟基末端恢复，对于铬酸盐抗性也很关键。Tdp1 的缺失可以减轻 pnk1Δ对铬酸盐的敏感性，同时增强对 Mus81 的需求。因此，Tdp1 和 PNKP 可以修复导致人类神经退行性变的重要一类 Cr 诱导的 SSB，从而防止复制叉崩溃。

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