Genome-Wide CRISPR Screens Reveal ZATT as a Synthetic Lethal Target of TOP2-Poison Etoposide That Can Act in a TDP2-Independent Pathway.
Genome-Wide CRISPR Screens Reveal ZATT as a Synthetic Lethal Target of TOP2-Poison Etoposide That Can Act in a TDP2-Independent Pathway.
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DOI：
10.3390/ijms24076545
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发表时间：
2023-03-31
影响因子：
5.6
通讯作者：
Chen, Junjie
中科院分区：
文献类型：
--
作者：
Park, Jeong-Min;Zhang, Huimin;Nie, Litong;Wang, Chao;Huang, Min;Feng, Xu;Tang, Mengfan;Chen, Zhen;Xiong, Yun;Lee, Namsoo;Li, Siting;Yin, Ling;Hart, Traver;Chen, Junjie
依托泊苷（ETO）是一种靶向拓扑异构酶II（TOP2）的抗癌药物。它稳定了通常瞬时的TOP 2-DNA共价复合物（TOP 2cc），从而导致DNA双链断裂（DSB）。酪氨酰-DNA磷酸二酯酶2（TDP 2）通过从DSB的5′-末端去除磷酸酪氨酰肽而直接参与TOP2 cc的修复。最近的研究表明，TOP2 cc修复还需要其他因素，包括蛋白酶体和与TDP 2和TOP2相关的锌指蛋白，称为ZATT。ZATT可以改变TOP2 cc的构象，使得TDP 2可用于去除TOP2 cc。在这项研究中，我们的全基因组成簇规则间隔短回文重复序列（CRISPR）筛选显示，ZATT在ETO处理后促进细胞存活方面也具有TDP 2独立作用。ZATT KO细胞显示出比TDP 2-KO细胞相对更高的ETO敏感性，并且ZATT/TDP 2 DKO细胞显示出对ETO处理的附加超敏性。使用ZATT的一系列缺失突变体的研究确定，ZATT的N-末端1-168个残基是与TOP 2相互作用所必需的，并且这种相互作用对ETO敏感性至关重要。此外，ZATT的耗尽导致ETO或放线菌酮（CHX）处理后加速TOP 2降解，表明ZATT可能增加TOP 2的稳定性，并可能参与TOP 2的周转。总之，本研究表明，ZATT是决定ETO治疗和靶向反应的关键决定因素。ZATT是一种很有前途的策略，可提高ETO治疗癌症的疗效。
Etoposide (ETO) is an anticancer drug that targets topoisomerase II (TOP2). It stabilizes a normally transient TOP2–DNA covalent complex (TOP2cc), thus leading to DNA double-strand breaks (DSBs). Tyrosyl-DNA phosphodiesterases two (TDP2) is directly involved in the repair of TOP2cc by removing phosphotyrosyl peptides from 5′-termini of DSBs. Recent studies suggest that additional factors are required for TOP2cc repair, which include the proteasome and the zinc finger protein associated with TDP2 and TOP2, named ZATT. ZATT may alter the conformation of TOP2cc in a way that renders the accessibility of TDP2 for TOP2cc removal. In this study, our genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screens revealed that ZATT also has a TDP2-independent role in promoting cell survival following ETO treatment. ZATT KO cells showed relatively higher ETO sensitivity than TDP2-KO cells, and ZATT/TDP2 DKO cells displayed additive hypersensitivity to ETO treatment. The study using a series of deletion mutants of ZATT determined that the N-terminal 1–168 residues of ZATT are required for interaction with TOP2 and this interaction is critical to ETO sensitivity. Moreover, depletion of ZATT resulted in accelerated TOP2 degradation after ETO or cycloheximide (CHX) treatment, suggesting that ZATT may increase TOP2 stability and likely participate in TOP2 turnover. Taken together, this study suggests that ZATT is a critical determinant that dictates responses to ETO treatment and targeting. ZATT is a promising strategy to increase ETO efficacy for cancer therapy.
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影响因子：
14.9
作者：
Kiianitsa K;Maizels N
通讯作者：
Maizels N
DOI：
10.1126/science.aam6468
发表时间：
2017-09-29
期刊：
Science (New York, N.Y.)
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影响因子：
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作者：
Jin, Miaomiao;Li, Jingyu;Cao, Ying
通讯作者：
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