Nucleolar GTPase Bms1 displaces Ttf1 from RFB-sites to balance progression of rDNA transcription and replication

• 作者: Yanqing Zhu Yong Wang Boxiang Tao Jinhua Han Hong Chen Qinfang Zhu Ling Huang Yinan He Jian Hong Yunqin Li Jun Chen Jun Huang Li Jan Lo Jinrong Peng
• 来源期刊: 分子细胞生物学报（英文版）
• 年，卷（期）: 2021,（12）
• 所属期刊栏目: Articles
• 页码范围: 902-917
• 页数: 16页
• 语种: 英文
• DOI: 10.1093/jmcb/mjab074

摘要

18S,5.8S,and 28S ribosomal RNAs (rRNAs) are cotranscribed as a pre-ribosomal RNA (pre-rRNA) from the rDNA by RNA polymer-ase I whose activity is vigorous during the S-phase,leading to a conflict with rDNA replication.This conflict is resolved partly by replication-fork-barrier (RFB)-sites sequences located downstream of the rDNA and RFB-binding proteins such as Ttf1.However,how Ttf1 is displaced from RFB-sites to allow replication fork progression remains elusive.Here,we reported that loss-of-function of Bms1l,a nucleolar GTPase,upregulates rDNA transcription,causes replication-fork stall,and arrests cell cycle at the S-to-G2 transition;however,the G1-to-S transition is constitutively active characterized by persisting DNA synthesis.Concomitantly,ubf,tif-ⅠA,and taf1b marking rDNA transcription,Chk2,Rad51,and p53 marking DNA-damage response,and Rpa2,PCNA,Fen1,and Ttf1 marking replication fork stall are all highly elevated in bms1l mutants.We found that Bms1 interacts with Ttf1 in addition to Rc1l.Finally,we identified RFB-sites for zebrafish Ttf1 through chromatin immunoprecipitation sequencing and showed that Bms1 disassociates the Ttf1-RFB complex with its GTPase activity.We propose that Bms1 functions to balance rDNA transcrip-tion and replication at the S-phase through interaction with Rcl1 and Ttf1,respectively.TTF1 and Bms1 together might impose an S-phase checkpoint at the rDNA loci.