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Nucleolar GTPase Bms1 displaces Ttf1 from RFB-sites to balance progression of rDNA transcription and replication
Yanqing Zhu1,† , Yong Wang2,†,* , Boxiang Tao1 , Jinhua Han3 , Hong Chen1 , Qinfang Zhu1 , Ling Huang1 , Yinan He1 , Jian Hong4 , Yunqin Li4 , Jun Chen5 , Jun Huang3,* , Li Jan Lo1,* , Jinrong Peng1,*
1MOE Key Laboratory for Molecular Animal Nutrition, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
2Taizhou Hospital, Zhejiang University, Taizhou 317000, China
3The MOE Key Laboratory of Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
4Institute of Biotechnology, Zhejiang University, Hangzhou 310058, China
5College of Life Sciences, Zhejiang University, Hangzhou 310058, China
These authors contributed equally to this work.
*Correspondence to:Yong Wang , Jun Huang , Li Jan Lo , Jinrong Peng ,
J Mol Cell Biol, Volume 13, Issue 12, December 2021, 902-917,
Keyword: Bms1, cell cycle, nucleolus, ribosome small subunit processome, replication-fork barrier, Ttf1, zebrafish

18S, 5.8S, and 28S ribosomal RNAs (rRNAs) are cotranscribed as a pre-ribosomal RNA (pre-rRNA) from the rDNA by RNA polymerase 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 transcription 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.