小柯机器人

德国马克思普朗克生物物理化学研究所Cramer. Patrick小组取得一项新突破。他们揭示了人类转录-DNA修复偶联的结构基础。相关论文于2021年9月15日在线发表在《自然》杂志上。

在本研究中，研究人员解析了RNA聚合酶II(Pol II)转录复合物的五种高分辨率结构，其中包含人类转录偶联的DNA修复因子和延伸因子PAF1复合物 (PAF) 和SPT6。整合生化实验与已发表的数据，这些结构提供了转录-修复耦合的新模型。Pol II在DNA损伤处的停滞会引起Cockayne综合征蛋白CSB替换延伸因子DSIF、CSB与PAF结合并将上游DNA移动到SPT6。由此产生的延伸复合物ECTCR使用CSA诱导的CSB转位酶活性来拉动上游DNA并推动Pol II向前。

如果无法绕过这些损伤位点，CRL4CSA会跨越Pol II钳夹并泛素化RPB1的K1268残基，从而将TFIIH招募到紫外线诱导的支架蛋白A (UVSSA)和完成DNA修复。CRL4CSA的构象变化导致CSB泛素化和转录偶联DNA修复因子的释放，随后转录可能会继续过度修复DNA。

研究人员表示，转录与DNA修复相偶联从而去除基因组中大量损伤的DNA以保护细胞免受紫外线(UV)照射的影响。当Pol II在DNA损伤处停滞时，其招募 Cockayne综合征蛋白CSB、E3泛素连接酶、CRL4CSA和UVSSA，开启转录偶联的DNA修复。

附：英文原文

Title: Structural basis of human transcription–DNA repair coupling

Author: Kokic, Goran, Wagner, Felix R., Chernev, Aleksandar, Urlaub, Henning, Cramer, Patrick

Issue&Volume: 2021-09-15

Abstract: Transcription-coupled DNA repair removes bulky DNA lesions from the genome1,2 and protects cells against ultraviolet (UV) irradiation3. Transcription-coupled DNA repair begins when RNA polymerase II (Pol II) stalls at a DNA lesion and recruits the Cockayne syndrome protein CSB, the E3 ubiquitin ligase, CRL4CSA and UV-stimulated scaffold protein A (UVSSA)3. Here we provide five high-resolution structures of Pol II transcription complexes containing human transcription-coupled DNA repair factors and the elongation factors PAF1 complex (PAF) and SPT6. Together with biochemical and published3,4 data, the structures provide a model for transcription–repair coupling. Stalling of Pol II at a DNA lesion triggers replacement of the elongation factor DSIF by CSB, which binds to PAF and moves upstream DNA to SPT6. The resulting elongation complex, ECTCR, uses the CSA-stimulated translocase activity of CSB to pull on upstream DNA and push Pol II forward. If the lesion cannot be bypassed, CRL4CSA spans over the Pol II clamp and ubiquitylates the RPB1 residue K1268, enabling recruitment of TFIIH to UVSSA and DNA repair. Conformational changes in CRL4CSA lead to ubiquitylation of CSB and to release of transcription-coupled DNA repair factors before transcription may continue over repaired DNA.

DOI: 10.1038/s41586-021-03906-4

Source: https://www.nature.com/articles/s41586-021-03906-4

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