Ribosome biogenesis,which takes place mainly in the nucleolus,involves coordinated expression of preribosomal RNAs(pre-rRNAs)and ribosomal proteins,pre-rRNA processing,and subunit assembly with the aid of numerous ass...Ribosome biogenesis,which takes place mainly in the nucleolus,involves coordinated expression of preribosomal RNAs(pre-rRNAs)and ribosomal proteins,pre-rRNA processing,and subunit assembly with the aid of numerous assembly factors.Our previous study showed that the Arabidopsis thaliana protein arginine methyltransferase AtPRMT3 regulates pre-rRNA processing;however,the underlying molecular mechanism remains unknown.Here,we report that AtPRMT3 interacts with Ribosomal Protein S2(RPS2),facilitating processing of the 90S/Small Subunit(SSU)processome and repressing nucleolar stress.We isolated an intragenic suppressor of atprmt3-2,which rescues the developmental defects of atprmt3-2 while produces a putative truncated AtPRMT3 protein bearing the entire N-terminus but lacking an intact enzymatic activity domain We further identified RPS2 as an interacting partner of AtPRMT3,and found that loss-of-function rps2a2b mutants were phenotypically reminiscent of atprmt3,showing pleiotropic developmental defects and aberrant pre-rRNA processing.RPS2B binds directly to pre-rRNAs in the nucleus,and such binding is enhanced in atprmt3-2.Consistently,multiple components of the 90S/SSU processome were more enriched by RPS2B in atprmt3-2,which accounts for early pre-rRNA processing defects and results in nucleolar stress.Collectively,our study uncovered a novel mechanism by which AtPRMT3 cooperates with RPS2B to facilitate the dynamic assembly/disassembly of the 90S/SSU processome during ribosome biogenesis and repress nucleolar stress.展开更多
Pancreatic ductal adenocarcinoma is a devastating disease with a poor prognosis regardless of stage. To date the mainstay of therapy for advanced disease has been chemotherapy with little incremental im-provements in ...Pancreatic ductal adenocarcinoma is a devastating disease with a poor prognosis regardless of stage. To date the mainstay of therapy for advanced disease has been chemotherapy with little incremental im-provements in outcome. Despite extensive research investigating new treatment options the current practices continue to utilise fluorouracil or gemcitabine containing combinations. The need for novel the-rapeutic approaches is mandated by the ongoing poor survival rates associated with this disease. One such approach may include manipulation of ribosome biogenesis and the nucleolar stress response, which has recently been applied to haematological malignancies such as lymphoma and prostate cancer with promising results. This review will focus on the current therapeutic options for pancreatic ductal adenocarcinoma and the complexities associated with developing novel treatments, with a particular emphasis on the role of the nucleolus as a treatment strategy.展开更多
Ribosomes are among the most fundamental molecular machines in all cells,as they are required for protein synthesis.Most structural rRNA components are generated in the nucleolus and assembled into pre-ribosomal parti...Ribosomes are among the most fundamental molecular machines in all cells,as they are required for protein synthesis.Most structural rRNA components are generated in the nucleolus and assembled into pre-ribosomal particles.Here we show Apak,a previously identified p53 inhibitor,as a novel ribosomal stress response protein.In unstressed cells,Apak is bound to the deSUMOylase SENP1 in the nucleoplasm and targeted for proteasomal degradation by MDM2 ubiquitin ligase.Upon ribosomal stress,SENP1 dissociates fromApak and the tumor suppressor protein ARF couplesUbc9 with Apak to promote Apak SUMOylation on zinc fingers.This results in Apak protein stabilization and translocation to the nucleolus,where Apak inhibits the pre-rRNA synthesis.These findings provide a molecular mechanism whereby ARF coordinates Apak to regulate ribosome biogenesis upon cellular stress.展开更多
基金This work was supported by grants from the National Natural Science Foundation of China(31788103 and 91540203 to X.Cao,31770874 to C.L.,31900932 to R.H.,and 31701096 to J.S.),Chinathe Strategic Priority Research Program of Chinese Academy of Sciences(XDB27030201 to X.Cao),China+1 种基金the Key Research Program of Frontier Sciences of Chinese Academy of Sciences(QYZDY-SSW-SMC022 to X.Cao),Chinathe State Key Laboratory of Plant Genomics,China.
文摘Ribosome biogenesis,which takes place mainly in the nucleolus,involves coordinated expression of preribosomal RNAs(pre-rRNAs)and ribosomal proteins,pre-rRNA processing,and subunit assembly with the aid of numerous assembly factors.Our previous study showed that the Arabidopsis thaliana protein arginine methyltransferase AtPRMT3 regulates pre-rRNA processing;however,the underlying molecular mechanism remains unknown.Here,we report that AtPRMT3 interacts with Ribosomal Protein S2(RPS2),facilitating processing of the 90S/Small Subunit(SSU)processome and repressing nucleolar stress.We isolated an intragenic suppressor of atprmt3-2,which rescues the developmental defects of atprmt3-2 while produces a putative truncated AtPRMT3 protein bearing the entire N-terminus but lacking an intact enzymatic activity domain We further identified RPS2 as an interacting partner of AtPRMT3,and found that loss-of-function rps2a2b mutants were phenotypically reminiscent of atprmt3,showing pleiotropic developmental defects and aberrant pre-rRNA processing.RPS2B binds directly to pre-rRNAs in the nucleus,and such binding is enhanced in atprmt3-2.Consistently,multiple components of the 90S/SSU processome were more enriched by RPS2B in atprmt3-2,which accounts for early pre-rRNA processing defects and results in nucleolar stress.Collectively,our study uncovered a novel mechanism by which AtPRMT3 cooperates with RPS2B to facilitate the dynamic assembly/disassembly of the 90S/SSU processome during ribosome biogenesis and repress nucleolar stress.
文摘Pancreatic ductal adenocarcinoma is a devastating disease with a poor prognosis regardless of stage. To date the mainstay of therapy for advanced disease has been chemotherapy with little incremental im-provements in outcome. Despite extensive research investigating new treatment options the current practices continue to utilise fluorouracil or gemcitabine containing combinations. The need for novel the-rapeutic approaches is mandated by the ongoing poor survival rates associated with this disease. One such approach may include manipulation of ribosome biogenesis and the nucleolar stress response, which has recently been applied to haematological malignancies such as lymphoma and prostate cancer with promising results. This review will focus on the current therapeutic options for pancreatic ductal adenocarcinoma and the complexities associated with developing novel treatments, with a particular emphasis on the role of the nucleolus as a treatment strategy.
基金This research was supported by grants from the National Basic Research Program of China(2011CB910802,2013CB910803,2012CB910702)the National Natural Science Foundation of China(31125010,81221004).
文摘Ribosomes are among the most fundamental molecular machines in all cells,as they are required for protein synthesis.Most structural rRNA components are generated in the nucleolus and assembled into pre-ribosomal particles.Here we show Apak,a previously identified p53 inhibitor,as a novel ribosomal stress response protein.In unstressed cells,Apak is bound to the deSUMOylase SENP1 in the nucleoplasm and targeted for proteasomal degradation by MDM2 ubiquitin ligase.Upon ribosomal stress,SENP1 dissociates fromApak and the tumor suppressor protein ARF couplesUbc9 with Apak to promote Apak SUMOylation on zinc fingers.This results in Apak protein stabilization and translocation to the nucleolus,where Apak inhibits the pre-rRNA synthesis.These findings provide a molecular mechanism whereby ARF coordinates Apak to regulate ribosome biogenesis upon cellular stress.
