Implications of inhibition of Rev1 interaction with Y family DNA polymerases for cisplatin chemotherapy.
Implications of inhibition of Rev1 interaction with Y family DNA polymerases for cisplatin chemotherapy.
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DOI：
10.1101/gad.348662.121
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发表时间：
2021-09-01
影响因子：
10.5
通讯作者：
Prakash S
中科院分区：
文献类型：
--
作者：
Yoon JH;Johnson RE;Prakash L;Prakash S
在这项研究中，尹等人。着手研究正常细胞与癌细胞的跨损伤合成（TLS）机制。作者利用报告分析和敲低细胞报告说，在正常细胞中，Polη 或 Polι 依赖性途径可促进通过顺铂链内交联的 TLS，这两种途径都需要 Rev1 作为支架组件。相反，癌细胞需要 Rev1-Pol z。作者还表明，Rev1 抑制剂 JH-RE-06 消除了 Rev1 与 Y 家族 Pols 一起发挥作用的能力，导致各种情况下 TLS 的丢失，并增加正常细胞对顺铂的敏感性。由于毒性和继发性恶性肿瘤，顺铂化疗变得受到限制。原则上，可以通过靶向跨损伤合成（TLS）聚合酶（Pols）来改善治疗，Pols通过链内交联（顺铂诱导的主要DNA加合物）促进复制。然而，为了专门针对恶性肿瘤并对正常细胞产生最小的副作用，充分了解正常细胞与癌细胞中的 TLS 机制至关重要。我们发现，在正常细胞中，通过顺铂链内交联的 TLS 是由 Polη 或 Polι 依赖性途径促进的，这两种途径都需要 Rev1 作为支架组件。相反，癌细胞需要 Rev1-Pol z。我们的研究结果表明，最近发现的一种 Rev1 抑制剂 JH-RE-06 据称可以特异性破坏 Rev1 与 Pol z 的相互作用，从而通过癌细胞中的顺铂加合物阻断 TLS，同时也消除了 Rev1 与 Y 家族 Pols 一起发挥作用的能力，这意味着通过使正常细胞中的 Rev1 依赖性 TLS 失活，该抑制剂将加剧顺铂化疗药物的毒性和致瘤性。
In this study, Yoon et al. set out to study translesion synthesis (TLS) mechanisms in normal versus cancer cells. Using reporter assays and knockdown cells, the authors report that in normal cells, TLS through cisplatin intrastrand cross-links is promoted by Polη- or Polι- dependent pathways, both of which require Rev1 as a scaffolding component. In contrast, cancer cells require Rev1-Polζ. The authors also show that the Rev1 inhibitor JH-RE-06 abrogates Rev1's ability to function with Y family Pols, leading to loss of TLS in various contexts and increased sensitivity to cisplatin in normal cells. Chemotherapy with cisplatin becomes limiting due to toxicity and secondary malignancies. In principle, therapeutics could be improved by targeting translesion synthesis (TLS) polymerases (Pols) that promote replication through intrastrand cross-links, the major cisplatin-induced DNA adduct. However, to specifically target malignancies with minimal adverse effects on normal cells, a good understanding of TLS mechanisms in normal versus cancer cells is paramount. We show that in normal cells, TLS through cisplatin intrastrand cross-links is promoted by Polη- or Polι-dependent pathways, both of which require Rev1 as a scaffolding component. In contrast, cancer cells require Rev1-Polζ. Our findings that a recently identified Rev1 inhibitor, JH-RE-06, purported to specifically disrupt Rev1 interaction with Polζ to block TLS through cisplatin adducts in cancer cells, abrogates Rev1's ability to function with Y family Pols as well, implying that by inactivating Rev1-dependent TLS in normal cells, this inhibitor will exacerbate the toxicity and tumorigenicity of chemotherapeutics with cisplatin.
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影响因子：
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