The ARK2N–CK2 complex initiates transcription-coupled repair through enhancing the interaction of CSB with lesion-stalled RNAPII
Yefei Luo, Jia Li, Xiaoman Li, Haodong Lin, Zuchao Mao, Zhanzhan Xu, Shiwei Li, Chen Nie, Xiao Albert Zhou, Junwei Liao, Yundong Xiong, Xingzhi Xu, Jiadong Wang
Abstract
Transcription is extremely important for cellular processes but can be hindered by RNA polymerase II (RNAPII) pausing and stalling. Cockayne syndrome protein B (CSB) promotes the progression of paused RNAPII or initiates transcription-coupled nucleotide excision repair (TC-NER) to remove stalled RNAPII. However, the specific mechanism by which CSB initiates TC-NER upon damage remains unclear. In this study, we identified the indispensable role of the ARK2N–CK2 complex in the CSB-mediated initiation of TC-NER. The ARK2N–CK2 complex is recruited to damage sites through CSB and then phosphorylates CSB. Phosphorylation of CSB enhances its binding to stalled RNAPII, prolonging the association of CSB with chromatin and promoting CSA-mediated ubiquitination of stalled RNAPII. Consistent with this finding, Ark2n −/− mice exhibit a phenotype resembling Cockayne syndrome. These findings shed light on the pivotal role of the ARK2N–CK2 complex in governing the fate of RNAPII through CSB, bridging a critical gap necessary for initiating TC-NER.