The ARK2N-CK2 complex initiates transcription- coupled repair through enhancing the interaction of CSB with lesion- stalled RNAPII

• 成果类型: Article
• 署名作者: Luo, Yefei; Li, Jia; Li, Xiaoman; Lin, Haodong; Mao, Zuchao; Xu, Zhanzhan; Li, Shiwei; Nie, Chen; Zhou, Xiao Albert; Liao, Junwei; Xiong, Yundong; Xu, Xingzhi; Wang, Jiadong
• 署名单位: Peking University; Shenzhen University; Shenzhen University; Peking University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11862
• DOI: 10.1073/pnas.2404383121
• 发表日期: 2024-06-11
• 关键词: uv-sensitive syndrome; nucleotide excision-repair; syndrome b protein; dna-damage; polymerase-ii; factor csb/ercc6; atpase domain; yeast rad26; gene; elongation

摘要

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. Significance The malfunction of CSB results in Cockayne syndrome (CS), a severe genetic degenerative disorder. CSB plays contrasting roles: It facilitates RNAPII to bypass minor obstacles or triggers TC - NER for RNAPII removal in the presence of bulky DNA damage. However, the mechanism by which CSB determines the fate of RNAPII remains unclear. Our identification of ARK2N and CK2 as crucial TC - NER facilitators, by enhancing the interaction between CSB and RNAPII, sheds light on this critical decisionmaking process. Notably, Ark2n -/- knockout mice exhibit increased sensitivity to UV damage and degenerative traits, suggesting its potential as a CS - associated gene. By highlighting the key role of ARK2N-CK2 in initiating TC - NER, our research bridges a longstanding gap in understanding this essential pathway.