RIF1 acts as a gatekeeper of B cell identity during late differentiation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA995715 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25307100.fastq.gz | Fastqsanger.gz | |||
| SRR25307101.fastq.gz | Fastqsanger.gz | |||
| SRR25307102.fastq.gz | Fastqsanger.gz | |||
| SRR25307103.fastq.gz | Fastqsanger.gz | |||
| SRR25307104.fastq.gz | Fastqsanger.gz |
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Project description:RIF1 is a multifunctional protein that promotes immunoglobulin (Ig) isotype diversification. Whether RIF1 plays additional roles in adaptive immunity is unknown. In this study, we observed an upregulation of RIF1 expression following mature B cell activation, while its deficiency led to a deregulated expression profile enriched in genes typically expressed in B cell progenitors and plasma cells (PC). RIF1 ablation resulted in increased plasmablast formation ex vivo and enhanced terminal differentiation into PC upon immunization. Therefore, RIF1 serves as a cell identity gatekeeper during late B cell differentiation, providing an additional layer of control in the establishment of humoral immunity.
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Project description:RIF1 acts downstream of 53BP1 to coordinate DNA double strand break repair pathway choice between non-homologous end joining (NHEJ) and homologous recombination (HR). Here we identified ASF1 as an endogenous RIF1-associated protein. We showed that ASF1 forms complex with RIF1 and regulates RIF1-dependent functions in DNA damage response.
2022-06-09 | PXD027727 | Pride
Project description:Chromosomal DNA replication involves the coordinated activity of hundreds to thousands of replication origins. Individual replication origins are subject to epigenetic regulation of their activity during S-phase, resulting in differential efficiencies and timings of replication initiation during S-phase. This regulation is thought to involve chromatin structure and organization into timing domains with differential ability to recruit limiting replication factors. Rif1 has recently been identified as a genome-wide regulator of replication timing in fission yeast and in mammalian cells. However, previous studies in budding yeast have suggested that Rif1’s role in controlling replication timing may be limited to subtelomeric domains and derives from its established role in telomere length regulation. We have analyzed replication timing by analyzing BrdU incorporation genome-wide, and report that Rif1 regulates the timing of late/dormant replication origins throughout the S. cerevisiae genome. Analysis of pfa4∆ cells, which are defective in palmitoylation and membrane association of Rif1, suggests that replication timing regulation by Rif1 is independent of its role in localizing telomeres to the nuclear periphery. Intra-S checkpoint signaling is intact in rif1∆ cells, and checkpoint-defective mec1∆ cells do not comparably deregulate replication timing, together indicating that Rif1 regulates replication timing through a mechanism independent of this checkpoint. Our results indicate that the Rif1 mechanism regulates origin timing irrespective of proximity to a chromosome end, and suggest instead that telomere sequences merely provide abundant binding sites for proteins that recruit Rif1. Still, the abundance of Rif1 binding in telomeric domains may facilitate Rif1-mediated repression of non-telomeric origins that are more distal from centromeres.
2014-06-01 | GSE55130 | GEO
Project description:Chromosomal DNA replication involves the coordinated activity of hundreds to thousands of replication origins. Individual replication origins are subject to epigenetic regulation of their activity during S-phase, resulting in differential efficiencies and timings of replication initiation during S-phase. This regulation is thought to involve chromatin structure and organization into timing domains with differential ability to recruit limiting replication factors. Rif1 has recently been identified as a genome-wide regulator of replication timing in fission yeast and in mammalian cells. However, previous studies in budding yeast have suggested that Rif1’s role in controlling replication timing may be limited to subtelomeric domains and derives from its established role in telomere length regulation. We have analyzed replication timing by analyzing BrdU incorporation genome-wide, and report that Rif1 regulates the timing of late/dormant replication origins throughout the S. cerevisiae genome. Analysis of pfa4∆ cells, which are defective in palmitoylation and membrane association of Rif1, suggests that replication timing regulation by Rif1 is independent of its role in localizing telomeres to the nuclear periphery. Intra-S checkpoint signaling is intact in rif1∆ cells, and checkpoint-defective mec1∆ cells do not comparably deregulate replication timing, together indicating that Rif1 regulates replication timing through a mechanism independent of this checkpoint. Our results indicate that the Rif1 mechanism regulates origin timing irrespective of proximity to a chromosome end, and suggest instead that telomere sequences merely provide abundant binding sites for proteins that recruit Rif1. Still, the abundance of Rif1 binding in telomeric domains may facilitate Rif1-mediated repression of non-telomeric origins that are more distal from centromeres. 30 total samples: (6 samples - BrdU- HU arrest 45min with 2 replicates, strains: WT, rif1 delta, pfa4 delta) (12 samples -S-phase BrdU time course with 2 replicates at 25 and 35 min, strains: WT, rif1 delta, mec1_100) (12 samples - S-phase BrdU time course with 2 replicates at 25 and 35 min, strains: sml1 delta, sml1 delta rif1 delta, sml1 delta mec1 delta)
2014-06-01 | E-GEOD-55130 | biostudies-arrayexpress
Project description:Chromosomal DNA replication involves the coordinated activity of hundreds to thousands of replication origins. Individual replication origins are subject to epigenetic regulation of their activity during S-phase, resulting in differential efficiencies and timings of replication initiation during S-phase. This regulation is thought to involve chromatin structure and organization into timing domains with differential ability to recruit limiting replication factors. Rif1 has recently been identified as a genome-wide regulator of replication timing in fission yeast and in mammalian cells. However, previous studies in budding yeast have suggested that Rif1’s role in controlling replication timing may be limited to subtelomeric domains and derives from its established role in telomere length regulation. We have analyzed replication timing by analyzing BrdU incorporation genome-wide, and report that Rif1 regulates the timing of late/dormant replication origins throughout the S. cerevisiae genome. Analysis of pfa4∆ cells, which are defective in palmitoylation and membrane association of Rif1, suggests that replication timing regulation by Rif1 is independent of its role in localizing telomeres to the nuclear periphery. Intra-S checkpoint signaling is intact in rif1∆ cells, and checkpoint-defective mec1∆ cells do not comparably deregulate replication timing, together indicating that Rif1 regulates replication timing through a mechanism independent of this checkpoint. Our results indicate that the Rif1 mechanism regulates origin timing irrespective of proximity to a chromosome end, and suggest instead that telomere sequences merely provide abundant binding sites for proteins that recruit Rif1. Still, the abundance of Rif1 binding in telomeric domains may facilitate Rif1-mediated repression of non-telomeric origins that are more distal from centromeres.
2014-06-01 | GSE55155 | GEO
Project description:Chromosomal DNA replication involves the coordinated activity of hundreds to thousands of replication origins. Individual replication origins are subject to epigenetic regulation of their activity during S-phase, resulting in differential efficiencies and timings of replication initiation during S-phase. This regulation is thought to involve chromatin structure and organization into timing domains with differential ability to recruit limiting replication factors. Rif1 has recently been identified as a genome-wide regulator of replication timing in fission yeast and in mammalian cells. However, previous studies in budding yeast have suggested that Rif1’s role in controlling replication timing may be limited to subtelomeric domains and derives from its established role in telomere length regulation. We have analyzed replication timing by analyzing BrdU incorporation genome-wide, and report that Rif1 regulates the timing of late/dormant replication origins throughout the S. cerevisiae genome. Analysis of pfa4∆ cells, which are defective in palmitoylation and membrane association of Rif1, suggests that replication timing regulation by Rif1 is independent of its role in localizing telomeres to the nuclear periphery. Intra-S checkpoint signaling is intact in rif1∆ cells, and checkpoint-defective mec1∆ cells do not comparably deregulate replication timing, together indicating that Rif1 regulates replication timing through a mechanism independent of this checkpoint. Our results indicate that the Rif1 mechanism regulates origin timing irrespective of proximity to a chromosome end, and suggest instead that telomere sequences merely provide abundant binding sites for proteins that recruit Rif1. Still, the abundance of Rif1 binding in telomeric domains may facilitate Rif1-mediated repression of non-telomeric origins that are more distal from centromeres. 4 samples BrdU-IP-seq in HU, 2 strains with 2-replicates each (strains:WT and rif1 delta)
2014-06-01 | E-GEOD-55155 | biostudies-arrayexpress
Project description:The budding yeast telomere binding protein Rif1 (Rap1-interacting factor 1) plays an evolutionarily conserved role in the control of DNA replication timing, which operates through an interaction with the PP1 phosphatase. Rif1-PP1 has been proposed to inhibit origin firing by reversing the phosphorylation of key targets involved in replication initiation. However, it is not yet known if Rif1 binds directly to the replication origins that it controls. Here we show that in unperturbed yeast cells Rif1 primarily regulates late-replicating telomere-proximal origins. Using Chromatin Endogenous Cleavage (ChEC)-seq, we find that Rif1 is robustly detected at many late-replicating origins that we identify as targets of its inhibitory action. Abrogation of Rif1 telomere binding, through mutation of its Rap1 binding module, leads to increased Rif1 binding and late origin inhibition elsewhere in the genome. Our results support a model whereby Rif1 inhibits replication initiation by binding directly at origins, most of which are near telomeres, where Rif1 is concentrated through its interaction with telomere-bound Rap1 protein.
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Project description:The Rif1 protein negatively regulates telomeric TG repeat length in the budding yeast S. cerevisiae, but how it prevents telomere over-extension is unknown. Rif1 was recently shown to control DNA replication by acting as a Protein Phosphatase 1 (PP1)-targeting subunit. Therefore we investigated whether Rif1 controls telomere length by targeting PP1 activity. We find that a Rif1 mutant that cannot interact with PP1 causes a long-telomere phenotype, similar to that of rif1∆ cells. Compromised PP1 function also causes telomere extension. Tethering PP1 at a specific telomere partially substitutes for Rif1 in limiting TG repeat length, confirming the importance of PP1 in telomere length control. Ablating Rif1-PP1 interaction leads to precocious activation of telomere-proximal replication origins and aberrantly early telomere replication. However, we find that Rif1 still limits telomere length even if nearby replication origins are deleted, indicating that effects of Rif1 on telomere length are not mediated through replication timing. Instead we find that, even at a telomere created after DNA synthesis during a mitotic block, Rif1-PP1 interaction is required to suppress telomere lengthening and prevent inappropriate recruitment of Tel1 kinase. Overall, our results show that Rif1 controls telomere length by recruiting PP1 to directly suppress telomerase-mediated TG repeat lengthening.
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Project description:Control of DNA copy number is essential to maintain genome stability and ensure proper cell and tissue function. In Drosophila, the SNF2-domain-containing SUUR protein inhibits replication fork progression within specific regions of the genome to promote DNA underreplication. While dissecting the function of SUUR’s SNF2 domain, we identified a physical interaction between SUUR and Rif1. Rif1 has many roles in DNA metabolism and regulates the replication timing program. We demonstrate that repression of DNA replication is dependent on Rif1. Rif1 localizes to active replication forks in an SUUR-dependent manner and directly regulates replication fork progression. Importantly, SUUR associates with replication forks in the absence of Rif1, indicating that Rif1 acts downstream of SUUR to inhibit fork progression. Our findings uncover an unrecognized function of the Rif1 protein as a direct regulator of replication fork progression suggesting developmental regulation of Rif1 activity.
2018-10-15 | GSE114370 | GEO
Project description:B cell identity and function is dependent on the proteins residing in the B cell surfaceome and their respective nanoscale organization. Here we show that CD20 is a gatekeeper for B cell identity and function due to its control of the functional nanoscale organization of receptors within the B surfaceome and the resting state of B lymphocytes. CRISPR/Cas-based ablation of CD20 in Ramos B cells revealed that IgM class B cell antigen receptor (IgM-BCR) and the co-receptor CD19 are functionally interlinked in the absence of CD20. The resulting IgM-BCR/CD19 signalling synapse leads to transient B cell activation and the loss of B cell identity. Re-expression of CD20 involving an aptamer-controlled riboswitch restores resting-state B cell nanoscale organization and function. Treatment of naive human B cells with the anti-CD20 antibody Rituximab leads to transient B cell activation and formation of transiently activated IgM-BCR/CD19 signalling synapses providing new insights into the molecular mode of action of Rituximab. The loss of B cell identity due to CD20-deficiency is accompanied by a PAX5 to BLIMP-1 transcriptional switch and increased plasma cell development. This cellular B cell differentiation towards plasma B cells is mechanistically accompanied by a metabolic shift towards oxidative phosphorylation.
2020-06-18 | MSV000085605 | MassIVE