Tyrosine kinase c-Abl couples RNA polymerase II transcription to DNA double-strand breaks
Tyrosine kinase c-Abl couples RNA polymerase II transcription to DNA double-strand breaks
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DOI：
10.1093/nar/gkz024
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发表时间：
2019-04-23
影响因子：
14.9
通讯作者：
Gullerova, Monika
中科院分区：
文献类型：
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作者：
Burger, Kaspar;Schlackow, Margarita;Gullerova, Monika
DNA不断受到内源性和外源性损伤。各种类型的DNA修复抵消高毒性DNA双链断裂（DSB），以维持基因组稳定性。最近的研究表明，人类DNA损伤反应（DDR）利用小RNA种类，其作为长的非编码（nc）RNA前体产生并促进DSB的识别。然而，控制这种转录本生产的监管原则在很大程度上仍然难以捉摸。在这里，我们表明，Abelson酪氨酸激酶c-Abl/ABL 1导致形成的RNA聚合酶II（RNAPII）焦点，主要是在羧基末端结构域（CTD）残基Tyr 1磷酸化，在DSBs。CTD Tyr 1磷酸化RNAPII（CTD Y1 P）合成链特异性损伤应答转录物（DARTs），其通过DNA-RNA杂合中间体触发双链（ds）RNA中间体的形成，以促进p53结合蛋白1（53 BP 1）和DNA损伤检查点1（MDC 1）介导因子向内源性DSB的募集。干扰转录、c-Abl活性、DNA-RNA杂交体形成或dsRNA加工会损害CTD Y1 P病灶形成，减弱DART合成并延迟DDR因子和DSB信号传导的募集。总的来说，我们的数据提供了新的见解，在RNA依赖性DDR通过耦合DSB诱导的c-Abl活性RNAPII产生DARTs随后DSB识别。
DNA is constantly exposed to endogenous and exogenous damage. Various types of DNA repair counteract highly toxic DNA double-strand breaks (DSBs) to maintain genome stability. Recent findings suggest that the human DNA damage response (DDR) utilizes small RNA species, which are produced as long non-coding (nc)RNA precursors and promote recognition of DSBs. However, regulatory principles that control production of such transcripts remain largely elusive. Here we show that the Abelson tyrosine kinase c-Abl/ABL1 causes formation of RNA polymerase II (RNAPII) foci, predominantly phosphorylated at carboxy-terminal domain (CTD) residue Tyr1, at DSBs. CTD Tyr1-phosphorylated RNAPII (CTD Y1P) synthetizes strand-specific, damage-responsive transcripts (DARTs), which trigger formation of double-stranded (ds)RNA intermediates via DNA-RNA hybrid intermediates to promote recruitment of p53-binding protein 1 (53BP1) and Mediator of DNA damage checkpoint 1 (MDC1) to endogenous DSBs. Interference with transcription, c-Abl activity, DNA-RNA hybrid formation or dsRNA processing impairs CTD Y1P foci formation, attenuates DART synthesis and delays recruitment of DDR factors and DSB signalling. Collectively, our data provide novel insight in RNA-dependent DDR by coupling DSB-induced c-Abl activity on RNAPII to generate DARTs for consequent DSB recognition.