DNA replication is a complex and crucial biological process in eukaryotes.To facilitate the study of eukaryotic replication events,we present a database of eukaryotic DNA replication origins(DeOri),which collects geno...DNA replication is a complex and crucial biological process in eukaryotes.To facilitate the study of eukaryotic replication events,we present a database of eukaryotic DNA replication origins(DeOri),which collects genome-wide data on eukaryotic DNA replication origins currently available.With the rapid development of high-throughput experimental technology in recent years,the number of datasets in the new release of DeOri 10.0 increased from 10 to 151 and the number of sequences increased from 16,145 to 9,742,396.Besides nucleotide sequences and browser extensible data(BED)files,corresponding annotation files,such as coding sequences(CDSs),mRNAs,and other biological elements within replication origins,are also provided.The experimental techniques used for each dataset,as well as related statistical data,are also presented on web page.Differences in experimental methods,cell lines,and sequencing technologies have resulted in distinct replication origins,making it challenging to differentiate between cell-specific and non-specific replication origins.Based on multiple replication origin datasets at the species level,we scored and screened replication origins in Homo sapiens,Gallus gallus,Mus musculus,Drosophila melanogaster,and Caenorhabditis elegans.The screened regions with high scores were considered as species-conservative origins,which are integrated and presented as reference replication origins(rORIs).Additionally,we analyzed the distribution of relevant genomic elements associated with replication origins at the genome level,such as CpG island(CGI),transcription start site(TSS),and G-quadruplex(G4).These analysis results can be browsed and downloaded as needed at http://tubic.tju.edu.cn/deori/.展开更多
The replication of DNA is a complex biological process that is essential for life.Bacterial DNA replication is initiated at genomic loci referred to as replication origins(oriCs).Integrating the Z-curve method,DnaA bo...The replication of DNA is a complex biological process that is essential for life.Bacterial DNA replication is initiated at genomic loci referred to as replication origins(oriCs).Integrating the Z-curve method,DnaA box distribution,and comparative genomic analysis,we developed a web server to predict bacterial oriCs in 2008 called Ori-Finder,which is helpful to clarify the characteristics of bacterial oriCs.The oriCs of hundreds of sequenced bacterial genomes have been annotated in the genome reports using Ori-Finder and the predicted results have been deposited in DoriC,a manually curated database of oriCs.This has facilitated large-scale data mining of functional elements in oriCs and strand-biased analysis.Here,we describe Ori-Finder 2022 with updated prediction framework,interactive visualization module,new analysis module,and user-friendly interface.More species-specific indicator genes and functional elements of oriCs are integrated into the updated framework,which has also been redesigned to predict oriCs in draft genomes.The interactive visualization module displays more genomic information related to oriCs and their functional elements.The analysis module includes regulatory protein annotation,repeat sequence discovery,homologous oriC search,and strand-biased analyses.The redesigned interface provides additional customization options for oriC prediction.Ori-Finder 2022 is freely available at http://tubic.tju.edu.cn/Ori-Finder/and https://tubic.org/Ori-Finder/.展开更多
In eukaryote, nuclear structure is a key component forthe functions of eukaryotic cells. More and more evidencesshow that the nuclear structure plays important role in re-gulating DNA replication. The nuclear structur...In eukaryote, nuclear structure is a key component forthe functions of eukaryotic cells. More and more evidencesshow that the nuclear structure plays important role in re-gulating DNA replication. The nuclear structure providesa physical barrier for the replication licensing, participatesin the decision where DNA replication initiates, and orga-nizes replication proteins as replication factory for DNAreplication. Through these works, new concepts on theregulation of DNA replication have emerged, which willbe discussed in this minireview.展开更多
The minichromosome maintenance complex(MCM)DNA helicase is an important replicative factor during DNA replication.The proper chromatin loading of MCM is a key step to ensure replication initiation during S phase.Becau...The minichromosome maintenance complex(MCM)DNA helicase is an important replicative factor during DNA replication.The proper chromatin loading of MCM is a key step to ensure replication initiation during S phase.Because replication initiation is regulated by multiple biological cues,additional changes to MCM may provide better understanding towards this event.Here,we report that histidine methyltransferase SETD3 promotes DNA replication in a manner dependent on enzymatic activity.Nascent-strand sequencing(NS-seq)shows that SETD3 regulates replication initiation,as depletion of SETD3 attenuates early replication origins firing.Biochemical studies reveal that SETD3 binds MCM mainly during S phase,which is required for the CDT1-mediated chromatin loading of MCM.This MCM loading relies on histidine-459 methylation(H459me)on MCM7 which is catalyzed by SETD3.Impairment of H459 methylation attenuates DNA synthesis and chromatin loading of MCM.Furthermore,we show that CDK2 phosphorylates SETD3 at Serine-21 during the G1/S phase,which is required for DNA replication and cell cycle progression.These findings demonstrate a novel mechanism by which SETD3 methylates MCM to regulate replication initiation.展开更多
Chromosomal DNA replication is one of the central biological events occurring inside cells. Due to its large size, the replica-tion of genomic DNA in eukaryotes initiates at hundreds to tens of thousands of sites call...Chromosomal DNA replication is one of the central biological events occurring inside cells. Due to its large size, the replica-tion of genomic DNA in eukaryotes initiates at hundreds to tens of thousands of sites called DNA origins so that the replication could be completed in a limited time. Further, eukaryotic DNA replication is sophisticatedly regulated, and this regulation guarantees that each origin fires once per S phase and each segment of DNA gets duplication also once per cell cycle. The first step of replication initiation is the assembly of pre-replication complex （pre-RC）. Since 1973, four proteins, Cdc6/Cdcl8, MCM, ORC and Cdtl, have been extensively studied and proved to be pre-RC components. Recently, a novel pre-RC compo- nent called Sapl/Girdin was identified. Sapl/Girdin is required for loading Cdcl8/Cdc6 to origins for pre-RC assembly in the fission yeast and human cells, respectively. At the transition of G1 to S phase, pre-RC is activated by the two kinases, cy- clin-dependent kinase （CDK） and Dbf4-dependent kinase （DDK）, and subsequently, RPA, primase-polct, PCNA, topoisomer-ase, Cdc45, polδ and pole are recruited to DNA origins for creating two bi-directional replication forks and initiating DNA replication. As replication forks move along chromatin DNA, they frequently stall due to the presence of a great number of replication barriers on chromatin DNA, such as secondary DNA structures, protein/DNA complexes, DNA lesions, gene tran-scription. Stalled forks must require checkpoint regulation for their stabilization. Otherwise, stalled forks will collapse, which results in incomplete DNA replication and genomic instability. This short review gives a concise introduction regarding the current understanding of replication initiation and replication fork stabilization.展开更多
基金supported by the National Natural Science Foundation of China(Grant Nos.32270692,31801104,31571358)the National Key R&D Program of China(Grant No.2018YFA0903700).
文摘DNA replication is a complex and crucial biological process in eukaryotes.To facilitate the study of eukaryotic replication events,we present a database of eukaryotic DNA replication origins(DeOri),which collects genome-wide data on eukaryotic DNA replication origins currently available.With the rapid development of high-throughput experimental technology in recent years,the number of datasets in the new release of DeOri 10.0 increased from 10 to 151 and the number of sequences increased from 16,145 to 9,742,396.Besides nucleotide sequences and browser extensible data(BED)files,corresponding annotation files,such as coding sequences(CDSs),mRNAs,and other biological elements within replication origins,are also provided.The experimental techniques used for each dataset,as well as related statistical data,are also presented on web page.Differences in experimental methods,cell lines,and sequencing technologies have resulted in distinct replication origins,making it challenging to differentiate between cell-specific and non-specific replication origins.Based on multiple replication origin datasets at the species level,we scored and screened replication origins in Homo sapiens,Gallus gallus,Mus musculus,Drosophila melanogaster,and Caenorhabditis elegans.The screened regions with high scores were considered as species-conservative origins,which are integrated and presented as reference replication origins(rORIs).Additionally,we analyzed the distribution of relevant genomic elements associated with replication origins at the genome level,such as CpG island(CGI),transcription start site(TSS),and G-quadruplex(G4).These analysis results can be browsed and downloaded as needed at http://tubic.tju.edu.cn/deori/.
基金supported by the National Key R&D Program of China(Grant No.2018YFA0903700)the National Natural Science Foundation of China(Grant Nos.21621004 and 31571358).
文摘The replication of DNA is a complex biological process that is essential for life.Bacterial DNA replication is initiated at genomic loci referred to as replication origins(oriCs).Integrating the Z-curve method,DnaA box distribution,and comparative genomic analysis,we developed a web server to predict bacterial oriCs in 2008 called Ori-Finder,which is helpful to clarify the characteristics of bacterial oriCs.The oriCs of hundreds of sequenced bacterial genomes have been annotated in the genome reports using Ori-Finder and the predicted results have been deposited in DoriC,a manually curated database of oriCs.This has facilitated large-scale data mining of functional elements in oriCs and strand-biased analysis.Here,we describe Ori-Finder 2022 with updated prediction framework,interactive visualization module,new analysis module,and user-friendly interface.More species-specific indicator genes and functional elements of oriCs are integrated into the updated framework,which has also been redesigned to predict oriCs in draft genomes.The interactive visualization module displays more genomic information related to oriCs and their functional elements.The analysis module includes regulatory protein annotation,repeat sequence discovery,homologous oriC search,and strand-biased analyses.The redesigned interface provides additional customization options for oriC prediction.Ori-Finder 2022 is freely available at http://tubic.tju.edu.cn/Ori-Finder/and https://tubic.org/Ori-Finder/.
文摘In eukaryote, nuclear structure is a key component forthe functions of eukaryotic cells. More and more evidencesshow that the nuclear structure plays important role in re-gulating DNA replication. The nuclear structure providesa physical barrier for the replication licensing, participatesin the decision where DNA replication initiates, and orga-nizes replication proteins as replication factory for DNAreplication. Through these works, new concepts on theregulation of DNA replication have emerged, which willbe discussed in this minireview.
基金supported by the National Key Research and Development program of China(2023YF0913403)the National Natural Science Foundation of China(32200584,31971231)+1 种基金the Fundamental Research Funds for the Central Universities(2042022dx0003,2042022kf1048)the China Postdoctoral Science Foundation(2021M702526).
文摘The minichromosome maintenance complex(MCM)DNA helicase is an important replicative factor during DNA replication.The proper chromatin loading of MCM is a key step to ensure replication initiation during S phase.Because replication initiation is regulated by multiple biological cues,additional changes to MCM may provide better understanding towards this event.Here,we report that histidine methyltransferase SETD3 promotes DNA replication in a manner dependent on enzymatic activity.Nascent-strand sequencing(NS-seq)shows that SETD3 regulates replication initiation,as depletion of SETD3 attenuates early replication origins firing.Biochemical studies reveal that SETD3 binds MCM mainly during S phase,which is required for the CDT1-mediated chromatin loading of MCM.This MCM loading relies on histidine-459 methylation(H459me)on MCM7 which is catalyzed by SETD3.Impairment of H459 methylation attenuates DNA synthesis and chromatin loading of MCM.Furthermore,we show that CDK2 phosphorylates SETD3 at Serine-21 during the G1/S phase,which is required for DNA replication and cell cycle progression.These findings demonstrate a novel mechanism by which SETD3 methylates MCM to regulate replication initiation.
文摘Chromosomal DNA replication is one of the central biological events occurring inside cells. Due to its large size, the replica-tion of genomic DNA in eukaryotes initiates at hundreds to tens of thousands of sites called DNA origins so that the replication could be completed in a limited time. Further, eukaryotic DNA replication is sophisticatedly regulated, and this regulation guarantees that each origin fires once per S phase and each segment of DNA gets duplication also once per cell cycle. The first step of replication initiation is the assembly of pre-replication complex （pre-RC）. Since 1973, four proteins, Cdc6/Cdcl8, MCM, ORC and Cdtl, have been extensively studied and proved to be pre-RC components. Recently, a novel pre-RC compo- nent called Sapl/Girdin was identified. Sapl/Girdin is required for loading Cdcl8/Cdc6 to origins for pre-RC assembly in the fission yeast and human cells, respectively. At the transition of G1 to S phase, pre-RC is activated by the two kinases, cy- clin-dependent kinase （CDK） and Dbf4-dependent kinase （DDK）, and subsequently, RPA, primase-polct, PCNA, topoisomer-ase, Cdc45, polδ and pole are recruited to DNA origins for creating two bi-directional replication forks and initiating DNA replication. As replication forks move along chromatin DNA, they frequently stall due to the presence of a great number of replication barriers on chromatin DNA, such as secondary DNA structures, protein/DNA complexes, DNA lesions, gene tran-scription. Stalled forks must require checkpoint regulation for their stabilization. Otherwise, stalled forks will collapse, which results in incomplete DNA replication and genomic instability. This short review gives a concise introduction regarding the current understanding of replication initiation and replication fork stabilization.
