意大利的Pier Giuseppe Pelicci研究团队近期合作发现，在特定的基因组位点释放停顿RNA聚合酶II（RNA Pol II）易导致双链断裂的形成，并促进癌症相关的染色体易位。2019年6月，国际知名学术期刊《Nature Genetics》发表了这一成果。

目前，人们对于自发的DNA双链断裂是如何形成的，正常细胞如何应对这些断裂，以及这些断裂是否会影响癌症相关的染色体异位还不太清楚。

研究人员发现，在正常的乳腺细胞中释放处于启动子、5’端剪接位点以及活跃的增强子区域的停顿RNA Pol II时，双链断裂会发生并借助于经典的DNA损伤响应机制进行末端连接修复。逻辑/因果关联性数学模型显示，Poll II在长基因上的停顿既可以预测双链断裂的发生又是造成双链断裂的主因。损伤的内含子与停顿的Pol II、TOP2B和XRCC4等蛋白一起富集在染色体异位的断点处，此外，这些损伤也在拓扑相关结构域（TAD）边缘-两侧的区域被发现。因此，这项工作表明，在正常生长条件下，在特定位点和染色体边界释放处于停顿的Pol II会促进双链损伤的形成并引起染色体异位。

附：英文原文

Title: Release of paused RNA polymerase II at specific loci favors DNA double-strand-break formation and promotes cancer translocations

Author: Gaetano Ivan Dellino, Fernando Palluzzi, Andrea Maria Chiariello, Rossana Piccioni, Simona Bianco, Laura Furia, Giulia De Conti, Britta A. M. Bouwman, Giorgio Melloni, Davide Guido, Luciano Giac, Lucilla Luzi, Davide Cittaro, Mario Faretta, Mario Nicodemi, Nicola Crosetto, Pier Giuseppe Pelicci

Issue&Volume: Volume 51 Issue 6, June 2019

Abstract: It is not clear how spontaneous DNA double-strand breaks (DSBs) form and are processed in normal cells, and whether they predispose to cancer-associated translocations. We show that DSBs in normal mammary cells form upon release of paused RNA polymerase II (Pol II) at promoters, 5 splice sites and active enhancers, and are processed by end-joining in the absence of a canonical DNA-damage response. Logistic and causal-association models showed that Pol II pausing at long genes is the main predictor and determinant of DSBs. Damaged introns with paused Pol II-pS5, TOP2B and XRCC4 are enriched in translocation breakpoints, and map at topologically associating domain boundary-flanking regions showing high interaction frequencies with distal loci. Thus, in unperturbed growth conditions, release of paused Pol II at specific loci and chromatin territories favors DSB formation, leading to chromosomal translocations.

DOI: 10.1038/s41588-019-0421-z

Source:https://www.nature.com/articles/s41588-019-0421-z