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TDRD3 promotes DHX9 chromatin recruitment and R-loop resolution
Nucleic Acids Research ( IF 16.6 ) Pub Date : 2021-07-20 , DOI: 10.1093/nar/gkab642
Wei Yuan 1 , Qais Al-Hadid 1 , Zhihao Wang 1 , Lei Shen 1 , Hyejin Cho 2 , Xiwei Wu 2 , Yanzhong Yang 1
Affiliation  

R-loops, which consist of a DNA/RNA hybrid and a displaced single-stranded DNA (ssDNA), are increasingly recognized as critical regulators of chromatin biology. R-loops are particularly enriched at gene promoters, where they play important roles in regulating gene expression. However, the molecular mechanisms that control promoter-associated R-loops remain unclear. The epigenetic ‘reader’ Tudor domain-containing protein 3 (TDRD3), which recognizes methylarginine marks on histones and on the C-terminal domain of RNA polymerase II, was previously shown to recruit DNA topoisomerase 3B (TOP3B) to relax negatively supercoiled DNA and prevent R-loop formation. Here, we further characterize the function of TDRD3 in R-loop metabolism and introduce the DExH-box helicase 9 (DHX9) as a novel interaction partner of the TDRD3/TOP3B complex. TDRD3 directly interacts with DHX9 via its Tudor domain. This interaction is important for recruiting DHX9 to target gene promoters, where it resolves R-loops in a helicase activity-dependent manner to facilitate gene expression. Additionally, TDRD3 also stimulates the helicase activity of DHX9. This stimulation relies on the OB-fold of TDRD3, which likely binds the ssDNA in the R-loop structure. Thus, DHX9 functions together with TOP3B to suppress promoter-associated R-loops. Collectively, these findings reveal new functions of TDRD3 and provide important mechanistic insights into the regulation of R-loop metabolism.

中文翻译:

TDRD3 促进 DHX9 染色质募集和 R 环分辨率

R 环由 DNA/RNA 杂合体和置换的单链 DNA (ssDNA) 组成,越来越多地被认为是染色质生物学的关键调节因子。R 环在基因启动子处特别丰富,它们在调节基因表达中发挥重要作用。然而,控制启动子相关 R 环的分子机制仍不清楚。表观遗传“阅读器”含有 Tudor 结构域的蛋白 3 (TDRD3) 可识别组蛋白和 RNA 聚合酶 II 的 C 端结构域上的甲基精氨酸标记,之前已显示募集 DNA 拓扑异构酶 3B (TOP3B) 以松弛负超螺旋 DNA 和防止R-loop的形成。在这里,我们进一步描述了 TDRD3 在 R 环代谢中的功能,并引入了 DExH-box 解旋酶 9 (DHX9) 作为 TDRD3/TOP3B 复合物的新型相互作用伙伴。TDRD3 通过其 Tudor 结构域直接与 DHX9 相互作用。这种相互作用对于将 DHX9 招募到目标基因启动子很重要,它以解旋酶活性依赖的方式解析 R 环以促进基因表达。此外,TDRD3 还刺激 DHX9 的解旋酶活性。这种刺激依赖于 TDRD3 的 OB 折叠,它可能在 R 环结构中结合 ssDNA。因此,DHX9 与 TOP3B 一起发挥作用以抑制启动子相关的 R 环。总的来说,这些发现揭示了 TDRD3 的新功能,并为 R 环代谢的调节提供了重要的机制见解。TDRD3 还刺激 DHX9 的解旋酶活性。这种刺激依赖于 TDRD3 的 OB 折叠,它可能在 R 环结构中结合 ssDNA。因此,DHX9 与 TOP3B 一起发挥作用以抑制启动子相关的 R 环。总的来说,这些发现揭示了 TDRD3 的新功能,并为 R 环代谢的调节提供了重要的机制见解。TDRD3 还刺激 DHX9 的解旋酶活性。这种刺激依赖于 TDRD3 的 OB 折叠,它可能在 R 环结构中结合 ssDNA。因此,DHX9 与 TOP3B 一起发挥作用以抑制启动子相关的 R 环。总的来说,这些发现揭示了 TDRD3 的新功能,并为 R 环代谢的调节提供了重要的机制见解。
更新日期:2021-07-20
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