Integrator 复合物在转录偶联修复后移除停滞的 RNA 聚合酶 II 以促进转录重启
Integrator complex removes lesion-stalled RNA polymerase II after transcription-coupled repair to facilitate transcription restart
研究发现 Integrator 复合物是处理被损伤停滞的 RNA 聚合酶 II（Pol II）的关键因子。互作蛋白质组学显示 Integrator 被招募到晚期 TC-NER 复合物中；其核酸内切酶核心可促进 DNA 损伤诱导后的转录恢复，但不影响 TC-NER 对损伤的切除。活细胞成像与染色质滞留实验表明，Integrator 在 TC-NER 后促使 Pol II 从 DNA 上释放。作者据此提出 Pol II 清除的两步机制：先由 TFIIH 介导的回退暴露损伤位点以供修复，随后由 Integrator 介导 Pol II 释放，从而恢复转录。
来源：Nucleic Acids Research · doi.org
Gene transcription by RNA Polymerase II (Pol II) is highly vulnerable to transcription-blocking DNA lesions (TBLs), which, if unresolved, induce transcription stress leading to cellular decline and aging. TBLs are removed by transcription-coupled nucleotide excision repair (TC-NER). TC-NER is initiated when Cockayne syndrome group B protein recognizes lesion-stalled Pol II and promotes TC-NER complex assembly. This complex recruits TFIIH for lesion verification, followed by incision and repair to enable transcription restart. Many TBLs stall Pol II within its active site, shielding the lesion from repair and requiring Pol II processing to expose it. However, whether this occurs through Pol II backtracking or release from the DNA, and the regulatory mechanisms involved, remain poorly defined. Here, we identified the Integrator complex as a key factor in lesion-stalled Pol II processing. Interaction proteomics revealed Integrator recruitment to late-stage TC-NER complexes. Integrator’s endonuclease core promotes efficient transcription recovery after TBL induction, without affecting lesion removal by TC-NER. Live-cell imaging and chromatin retention assays demonstrated that Integrator facilitates Pol II release from DNA following TC-NER. Collectively, these findings support a two-step mechanism for Pol II clearance during TC-NER, wherein TFIIH-mediated backtracking exposes the lesion for repair, followed by Integrator-mediated Pol II release to restore transcription.