SETD3-mediated histidine methylation of MCM7 regulates DNA replication by facilitating chromatin loading of MCM
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1020753 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26160541_1.fastq.gz | Fastqsanger.gz | |||
| SRR26160541_2.fastq.gz | Fastqsanger.gz | |||
| SRR26160542_1.fastq.gz | Fastqsanger.gz | |||
| SRR26160542_2.fastq.gz | Fastqsanger.gz | |||
| SRR26160543_1.fastq.gz | Fastqsanger.gz |
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Project description: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 G1/S phase. Because replication initiation is regulated by multiple biological cues, additional changes to MCM may provide deeper understanding towards this event. Here, we uncover that the histidine methyltransferase SETD3 promotes DNA replication in an enzymatic activity dependent manner. Nascent-strand sequencing (NS-seq) shows that SETD3 regulates replication initiation, as depletion of SETD3 attenuates early replication origins firing. Mechanistically, biochemical experiments reveal that SETD3 binds MCM mainly during G1/S phase, which is required for CDT1-mediated chromatin loading of MCM. The MCM loading relies on the histidine-459 methylation (H459me) on MCM7 that 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.
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Project description:Mono-methylation of histone H4 lysine 20 (H4K20me1) is increasingly appreciated to be critical for regulating genomic DNA replication, cell cycle progression and DNA damage repair. How exactly H4K20me1 regulates these biological processes remains murky. Here, we report that an evolutionarily conserved tandem Tudor domain (TTD) in the BAH Domain And Coiled-Coil Containing 1 (BAHCC1) protein (BAHCC1_TTD) selectively reads H4K20me1 for facilitating the replication origin activation and efficient DNA replication. Our integrated biochemical, structural, genomic and cellular analyses demonstrated that BAHCC1_TTD preferentially recognizes H4K20me1 to promote the recruitment of BAHCC1 and its interacting partners, notably the Mini-chromosome Maintenance (MCM) complex, to the replication origin sites. Combined actions of the H4K20me1-reading BAHCC1 and the H4K20me2-reading Origin Recognition Complex (ORC) ensure optimal genomic loading of MCM complexes for facilitating DNA replication. Depletion of BAHCC1, or disruption of the BAHCC1_TTD:H4K20me1 interaction, reduces levels of H4K20me1 and MCM loading, leading to defects in replication and cell cycle progression. Together, this study identifies BAHCC1_TTD as a conserved effector transducing the H4K20me1 signals to the recruitment of MCM complexes for facilitating efficient DNA replication.
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Project description:Minichromosome maintenance (MCM) proteins facilitate replication by licensing origins and unwinding the DNA double strand. Interestingly, the number of MCM hexamers greatly exceeds the number of firing origins suggesting additional roles of MCMs. Here we show a hitherto unanticipated function of MCM2 in cilia formation in human cells and zebrafish that is uncoupled from replication. Zebrafish depleted of MCM2 develop ciliopathy-phenotypes including microcephaly and aberrant heart looping due to malformed cilia. In non-cycling human fibroblasts, loss of MCM2 promotes transcription of a subset of genes, which cause cilia shortening and centriole overduplication. Chromatin immunoprecipitation experiments show that MCM2 binds to transcription start sites of cilia inhibiting genes. We propose that such binding may block RNA polymerase II-mediated transcription. Depletion of a second MCM (MCM7), which functions in complex with MCM2 during its canonical functions, reveals an overlapping cilia-deficiency phenotype likely unconnected to replication, although MCM7 appears to regulate a distinct subset of genes and pathways. Our data suggests that MCM2 and 7 exert a role in ciliogenesis in post-mitotic tissues.
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Project description:Methylation of histone H4 lysine 20 (H4K20), such as H4K20 mono-methylation (H4K20me1), regulates the biological processes of DNA replication, cell cycle progression, and DNA damage repair. Whereas H4K20me1 is knowingly written by SET8 (also known as PR-Set7) and erased by PHF8 (also known as KDM7B), the mechanism underlying H4K20me1-mediated regulation of DNA replication remains murky. Here, we report that a conserved tandem Tudor domain of BAHCC1 (BAHCC1TTD) specifically reads H4K20me1. Our biochemical, structural and cellular analyses demonstrated that the recognition of H4K20me1 by BAHCC1TTD facilitates the BAHCC1 recruitment onto the replication origins, where BAHCC1 interacts and recruits components of Minichromosome Maintenance (MCM) complex, a critical partner machinery of Origin Replication Complex (ORC) for mediating DNA replication. Combined actions of the H4K20me1-reading BAHCC1 and the H4K20me2-reading ORC ensure optimal genomic loading of MCM proteins. Depletion of BAHCC1, or disruption of BAHCC1TTD:H4K20me1 interaction, affected H4K20me1 homeostasis and MCM complex loading, leading to impaired DNA replication and defective cell cycle progression. Together, this study identifies a conserved BAHCC1TTD as an effector linking H4K20me1 to MCM recruitment for efficient DNA replication.
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Project description:we employed a TurboID approach that utilized a modified promiscuous biotin ligase BirA for proximity labeling by fusing SETD3 with this enzyme, By introducing biotin, cellular fractions of SETD3-TurboID-transfected cells, both cytosolic and chromatin fractions, underwent immunoprecipitation, followed by MS analysis to identify SETD3-interacting proteins. We conducted two experiments, first time we tested four samples, the RAW data of cyto_Vec and chr_Vec represented cells experssing emptry vector soluble fraction and chromatin fraction respectively. the RAW data of cyto_SET and chr_SET represented cells experssing SETD3-TurboID soluble fraction and chromatin fraction respectively. And PSMs.xlsx described the analysis of mass spectrum data. Second time we tested three samples. The RAW data of 21010704_DHG_VEC, 21010704_DHG_WT and 21010704_DHG_YA represented cells experssing emptry vector, SETD3-WT-TurboID or SETD3-Y313A-TurboID respectively. 21010704_DHG_Protein-compare.xlsx described the proteins identification of mass spectrum data. 21010704_DHG_Methyl-H.xlsx listed the histidine methylation identification of mass spectrum data.
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Project description:we employed a TurboID approach that utilized a modified promiscuous biotin ligase BirA for proximity labeling by fusing SETD3 with this enzyme, By introducing biotin, cellular fractions of SETD3-TurboID-transfected cells, both cytosolic and chromatin fractions, underwent immunoprecipitation, followed by MS analysis to identify SETD3-interacting proteins. We conducted two experiments, first time we tested four samples, the RAW data of cyto_Vec and chr_Vec represented cells experssing emptry vector soluble fraction and chromatin fraction respectively. the RAW data of cyto_SET and chr_SET represented cells experssing SETD3-TurboID soluble fraction and chromatin fraction respectively. And PSMs.xlsx described the analysis of mass spectrum data. Second time we tested three samples. The RAW data of 21010704_DHG_VEC, 21010704_DHG_WT and 21010704_DHG_YA represented cells experssing emptry vector, SETD3-WT-TurboID or SETD3-Y313A-TurboID respectively. 21010704_DHG_Protein-compare.xlsx described the proteins identification of mass spectrum data. 21010704_DHG_Methyl-H.xlsx listed the histidine methylation identification of mass spectrum data.
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Project description:Methylation of histone H4 lysine 20 (H4K20), such as H4K20 mono-methylation (H4K20me1), regulates the biological processes of DNA replication, cell cycle progression, and DNA damage repair1-4. Whereas H4K20me1 is knowingly written by SET85,6 (also known as PR-Set7) and erased by PHF87 (also known as KDM7B), the mechanism underlying H4K20me1-mediated regulation of DNA replication remains murky. Here, we report that a conserved tandem Tudor domain of BAHCC1 (BAHCC1TTD) specifically reads H4K20me1. Our biochemical, structural and cellular analyses demonstrated that the recognition of H4K20me1 by BAHCC1TTD facilitates the BAHCC1 recruitment onto the replication origins, where BAHCC1 interacts and recruits components of Minichromosome Maintenance (MCM) complex, a critical partner machinery of Origin Replication Complex (ORC) for mediating DNA replication8,9. Combined actions of the H4K20me1-reading BAHCC1 and the H4K20me2-reading ORC ensure optimal genomic loading of MCM proteins. Depletion of BAHCC1, or disruption of BAHCC1TTD:H4K20me1 interaction, affected H4K20me1 homeostasis and MCM complex loading, leading to impaired DNA replication and defective cell cycle progression. Together, this study identifies a conserved BAHCC1TTD as an effector linking H4K20me1 to MCM recruitment for efficient DNA replication.
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