Affinage

RIF1

Telomere-associated protein RIF1 · UniProt Q5UIP0

Length
2472 aa
Mass
274.5 kDa
Annotated
2026-04-28
100 papers in source corpus 45 papers cited in narrative 40 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RIF1 is a multifunctional genome maintenance factor that serves as a PP1 phosphatase-targeting subunit to regulate DNA replication timing, DNA double-strand break repair pathway choice, replication fork protection, and cytokinesis. In DNA repair, RIF1 is recruited to DSBs through direct phosphopeptide recognition of ATM-phosphorylated 53BP1 (requiring LxL-flanked doubly phosphorylated epitopes) and H3K4 methylation-dependent binding, where it inhibits 5′ end resection and promotes NHEJ in G1 by recruiting the shieldin complex via direct SHLD3 interaction and downstream CST–Polα fill-in machinery, while also engaging ASF1-mediated chromatin compaction to exclude BRCA1; BRCA1/CtIP antagonize RIF1 accumulation at DSBs in S/G2 (PMID:23333306, PMID:35216668, PMID:35439434, PMID:37306046, PMID:35177609, PMID:30022158). In replication, RIF1–PP1 counteracts DDK-mediated MCM helicase phosphorylation to establish the genome-wide replication timing program, stabilizes ORC1 to support origin licensing, protects stalled replication forks from DNA2–WRN nuclease degradation, and organizes late-replicating chromatin domains through G-quadruplex binding and oligomerization (PMID:24532715, PMID:28077461, PMID:31141682, PMID:26436827, PMID:29348174, PMID:26725008). RIF1–PP1 additionally controls abscission timing by dephosphorylating CHMP4C at the midbody to counteract Aurora B kinase (PMID:30905608).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2004 High

    The initial question of how human RIF1 participates in the DNA damage response was answered by showing it localizes to DSBs and dysfunctional telomeres in an ATM- and 53BP1-dependent manner and contributes to the intra-S-phase checkpoint, establishing RIF1 as a mammalian DDR factor distinct from its yeast telomeric role.

    Evidence Immunofluorescence foci analysis with siRNA knockdown and epistasis in human cells

    PMID:15342490

    Open questions at the time
    • Mechanism of RIF1 action at DSBs unknown
    • No information on repair pathway specificity
  2. 2009 High

    Two key advances addressed RIF1's roles at stalled forks and in telomere regulation: mammalian RIF1 was found at stalled replication forks with roles in HDR efficiency and S-phase progression, while yeast Rif1/Rif2 were shown to inhibit Tel1/ATM recruitment to telomeric DNA ends through distinct mechanisms.

    Evidence Conditional mouse knockout, siRNA, HDR reporter assays (mammalian); ChIP, genetic epistasis, two-hybrid (yeast)

    PMID:19217405 PMID:19948482

    Open questions at the time
    • Molecular mechanism of fork protection unknown
    • How RIF1 coordinates telomere and DSB functions unclear
  3. 2010 High

    The question of how RIF1 engages replication stress machinery was addressed by identifying RIF1 as a physical component of the BLM helicase complex, with its C-terminal domain providing a DNA-binding interface preferring branched structures.

    Evidence Reciprocal co-immunoprecipitation, in vitro DNA binding assays, genetic epistasis in DT40 cells

    PMID:20711169

    Open questions at the time
    • Functional significance of BLM-RIF1 interaction at forks not fully defined
    • Whether this interaction is separable from DSB repair function unknown
  4. 2012 High

    A foundational question—whether RIF1 has a genome-wide role in replication timing beyond telomeres—was resolved by demonstrating that RIF1 is a global determinant of the replication timing program in both fission yeast and human cells, binding late-replicating origins from M to G1 and controlling mid-S replication patterns and chromatin loop organization.

    Evidence ChIP-seq, genome-wide replication timing analysis, BrdU incorporation, chromatin fractionation in fission yeast and human cells

    PMID:22279046 PMID:22850673 PMID:22850674

    Open questions at the time
    • Enzymatic mechanism of replication delay unknown
    • How RIF1 selects late-firing origins unclear
  5. 2013 High

    The critical question of RIF1's role in DSB repair pathway choice was resolved: RIF1 acts as the key 53BP1 effector that inhibits 5′ end resection to promote NHEJ in G1, while BRCA1/CtIP antagonize RIF1 in S/G2; Rif1 knockout mice show severely compromised class switch recombination and telomere fusion, and Rif1 loss rescues BRCA1-deficient cells from toxic NHEJ and PARP inhibitor sensitivity.

    Evidence Co-IP, knockdown/rescue, cell cycle-specific foci assays, mouse knockout, CSR and telomere fusion assays across four independent laboratories

    PMID:23306437 PMID:23306439 PMID:23333305 PMID:23333306 PMID:23486525

    Open questions at the time
    • How RIF1 physically blocks resection machinery unknown
    • Downstream effectors of RIF1 at DSBs not identified
  6. 2013 High

    Structural understanding of yeast Rif1 at telomeres was established: crystal structures revealed Rif1 contains a tetramerization module and binds the Rap1 C-terminal domain at separable epitopes, creating higher-order architecture that interlinks Rap1 units.

    Evidence X-ray crystallography with biochemical and in vivo functional validation in budding yeast

    PMID:23746845

    Open questions at the time
    • Whether mammalian RIF1 forms analogous oligomeric structures unknown
    • Structure of full-length RIF1 not determined
  7. 2014 High

    The enzymatic mechanism by which RIF1 controls replication timing was identified: RIF1 recruits PP1 phosphatase via conserved RVxF and SILK motifs to reverse DDK-mediated MCM helicase phosphorylation, directly linking RIF1 to origin firing control; this was independently confirmed in budding yeast and extended to mammals.

    Evidence Genetic analysis, PP1 interaction assays, Mcm4/Sld3 phosphorylation analysis, mutagenesis of PP1-docking motifs in yeast; cruciform DNA binding by NMR for C-terminal domain

    PMID:24532715 PMID:24634216 PMID:24656819 PMID:24685139

    Open questions at the time
    • How PP1 targeting is regulated during cell cycle transitions unclear
    • Whether PP1-independent functions contribute to timing unknown
  8. 2014 High

    RIF1's epigenetic role was uncovered: in mouse embryonic stem cells, Rif1 maintains H3K9me3 at subtelomeric regions by stabilizing the H3K9 methylation complex, thereby repressing Zscan4 and regulating telomere length homeostasis.

    Evidence Co-immunoprecipitation, ChIP, shRNA knockdown, rescue experiments in mESCs

    PMID:24735877

    Open questions at the time
    • Whether this epigenetic function extends to non-telomeric loci unknown at this point
    • Direct vs. indirect role in H3K9me3 maintenance not resolved
  9. 2015 High

    The question of how RIF1 recognizes specific chromatin regions was addressed: fission yeast Rif1 binds G-quadruplex structures at intergenic regions to suppress replication over long distances, and mammalian Rif1 organizes late-replicating nuclear architecture through coating timing domains and restricting inter-domain interactions.

    Evidence ChIP-seq, in vitro G4 binding with mutagenesis, Hi-C, replication timing analysis

    PMID:26436827 PMID:26725008

    Open questions at the time
    • Whether G4 binding is the primary chromatin-targeting mechanism in mammals unclear
    • How RIF1 interfaces with lamina-associated domains not established
  10. 2015 High

    RIF1 was found to resolve ultrafine DNA bridges during anaphase in a PICH-dependent but 53BP1/BLM-independent manner, revealing a mitotic genome stability function.

    Evidence Immunofluorescence, siRNA knockdown, live-cell imaging, epistasis analysis in human cells

    PMID:26256213

    Open questions at the time
    • Molecular mechanism of UFB resolution by RIF1 unknown
    • Whether PP1 interaction is required for this function untested
  11. 2017 High

    Multiple advances consolidated the RIF1-PP1 axis: biophysical studies showed RIF1 is a high-affinity PP1 adaptor that outcompetes inhibitor-2; the dual role of RIF1-PP1 in both repressing MCM firing and protecting ORC1 from degradation in G1 was established; and structural analysis revealed the N-terminal domain forms a shepherd's crook fold that encases DNA as a head-to-tail dimer.

    Evidence NMR, ITC, SPR for PP1 binding; mass spectrometry phosphoproteomics and protein stability assays; crystal structure with functional mutagenesis; Xenopus egg extract reconstitution

    PMID:28077461 PMID:28273463 PMID:28522851 PMID:28604726

    Open questions at the time
    • Full-length RIF1-PP1 complex structure not determined
    • How PP1 substrate specificity is achieved through RIF1 unknown
  12. 2017 High

    RIF1's epigenetic functions were broadened to endogenous retroviruses: Rif1 directly occupies ERV regions and recruits histone methyltransferases to establish H3K9me3, H3K27me3, and DNA methylation, with the HEAT-like domain essential for this function.

    Evidence ChIP-seq, ATAC-seq, co-immunoprecipitation, gene deletion, methyltransferase recruitment assays

    PMID:29040764

    Open questions at the time
    • Whether ERV silencing depends on PP1 activity untested
    • Whether this function is conserved in human cells not confirmed
  13. 2018 High

    The downstream effector cascade of RIF1 at DSBs was completed by identifying the CST-Polα complex as acting downstream of 53BP1-RIF1-shieldin to fill in resected DNA and control repair pathway choice; separately, Drosophila studies revealed Cdk1-mediated phosphoregulation of Rif1 chromatin binding during replication timing.

    Evidence Co-IP, foci formation, RNAi, PARP inhibitor sensitivity (CST); live imaging, phosphomutant analysis (Drosophila)

    PMID:29746464 PMID:30022158

    Open questions at the time
    • How shieldin recruits CST to specific DSB sites not structurally resolved
    • Whether Cdk1 regulation of RIF1 is conserved in mammals unknown
  14. 2018 High

    Biochemical characterization of full-length murine RIF1 revealed it forms elongated homo-oligomers that bind G-quadruplex DNA with high specificity through both N- and C-terminal domains, with the central disordered region enhancing G4 affinity, providing a molecular basis for long-range chromatin organization.

    Evidence Purified protein hydrodynamic analysis, G4 binding assays, pulldown with purified full-length RIF1

    PMID:29348174

    Open questions at the time
    • In vivo significance of oligomerization for replication timing not directly tested
    • Stoichiometry of RIF1-G4 complexes at genomic loci unknown
  15. 2019 High

    RIF1-PP1 was shown to protect stalled/reversed replication forks from DNA2-WRN nuclease degradation by limiting WRN phosphorylation—a function independent of NHEJ—and separately, RIF1-PP1 was found to control cytokinetic abscission timing by dephosphorylating CHMP4C at the midbody to counteract Aurora B.

    Evidence DNA fiber assays, nascent DNA degradation assays, mutagenesis of PP1-binding motifs (fork protection); live-cell imaging, CHMP4C phosphorylation analysis (abscission)

    PMID:30905608 PMID:31141682 PMID:31337767

    Open questions at the time
    • How RIF1 is targeted to stalled forks versus DSBs remains unclear
    • Whether abscission control connects to genome integrity phenotypes not tested
  16. 2019 High

    In yeast, S-acylation of Rif1 by the palmitoyl acyltransferase Pfa4 was shown to facilitate its accumulation at DSBs at the inner nuclear membrane and promote NHEJ, providing a lipid-modification-based targeting mechanism.

    Evidence Mass spectrometry acylation detection, Pfa4 knockout, DSB repair assays, NHEJ assays in budding yeast

    PMID:31182712

    Open questions at the time
    • Whether mammalian RIF1 is similarly acylated not determined
    • Whether palmitoylation affects replication timing function unknown
  17. 2022 High

    Multiple studies resolved how RIF1 is recruited to DSBs and executes NHEJ: RIF1 directly recognizes doubly phosphorylated LxL epitopes on 53BP1, while a parallel H3K4me-dependent pathway (via SETD1A-BOD1L) stabilizes RIF1 at breaks; RIF1 also recruits ASF1 histone chaperone to compact chromatin and prevent BRCA1-mediated resection.

    Evidence Phosphopeptide binding assays, in vitro histone binding, ChIP, class switch recombination, HR/NHEJ reporter assays, chromatin compaction assays

    PMID:35177609 PMID:35216668 PMID:35439434

    Open questions at the time
    • Structural basis of RIF1-H3K4me interaction not determined at atomic resolution
    • Relative contributions of phospho-53BP1 vs. H3K4me pathways in different cell types unclear
  18. 2023 High

    The structural basis for shieldin recruitment was established: AlphaFold2-predicted and experimentally validated direct binding between the RIF1 HEAT-repeat domain and the SHLD3 eIF4E-like domain is essential for shieldin localization to DSBs, class switch recombination, and PARP inhibitor sensitivity.

    Evidence AlphaFold2 prediction validated by in vitro pulldown, cellular foci assays, CSR assays, PARP inhibitor sensitivity assays

    PMID:37306046

    Open questions at the time
    • High-resolution experimental structure of RIF1-SHLD3 complex not yet available
    • How RIF1 coordinates shieldin and ASF1 at the same DSB not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include: (1) how RIF1 is differentially targeted to DSBs versus replication forks versus the midbody; (2) the full-length structure of the RIF1-PP1 holoenzyme and its substrate selectivity mechanism; (3) whether RIF1's G4-binding and oligomerization properties directly organize mammalian replication timing domains in vivo; and (4) whether RIF1's epigenetic functions (H3K9me3, ERV silencing) are mechanistically linked to its PP1 activity.
  • No full-length RIF1-PP1 structure
  • No reconstitution of substrate selectivity in vitro
  • In vivo role of G4 binding in mammalian replication timing not directly tested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 9 GO:0060090 molecular adaptor activity 8 GO:0003677 DNA binding 5 GO:0042393 histone binding 1
Localization
GO:0005634 nucleus 7 GO:0005694 chromosome 4 GO:0005635 nuclear envelope 2
Pathway
R-HSA-69306 DNA Replication 9 R-HSA-73894 DNA Repair 7 R-HSA-4839726 Chromatin organization 3 R-HSA-1640170 Cell Cycle 2
Partners
ASF1ABLMCHMP4CCSBMAD2L2PPP1CASHLD3TP53BP1
Complex memberships
53BP1-RIF1-shieldinRIF1-PP1

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 RIF1 is recruited to DNA double-strand break (DSB) sites through ATM-dependent phosphorylation of 53BP1, acting as the critical downstream effector of 53BP1 to inhibit 5' end resection and promote NHEJ in G1 phase. BRCA1 and CtIP antagonize RIF1 accumulation at DSBs in S/G2 phase, and RIF1 depletion restores end resection and RAD51 loading in BRCA1-depleted cells. Co-immunoprecipitation, knockdown/rescue experiments, cell cycle phase-specific focus formation assays, RAD51 foci analysis Molecular cell High 23306437 23306439 23333305 23333306 23486525
2013 RIF1 is recruited to DSBs via the N-terminal phospho-SQ/TQ domain of 53BP1, and DSBs are hyperresected in the absence of RIF1; Rif1-/- mice show severely compromised 53BP1-dependent class switch recombination and fusion of dysfunctional telomeres. Deletion of Rif1 suppresses toxic NHEJ induced by PARP inhibition in Brca1-deficient cells. Mouse knockout, class switch recombination assays, telomere fusion assays, domain mapping Molecular cell High 23333305
2022 RIF1 is a phosphopeptide-binding protein that directly interacts with three phosphorylated 53BP1 epitopes sharing an essential LxL motif followed by two closely apposed phosphorylated residues. Simultaneous mutation of these sites abrogates RIF1 accumulation at IR-induced foci. RIF1 also modifies shieldin action independently of its 53BP1 interaction. Structural/biochemical characterization, phosphopeptide binding assays, mutagenesis, foci formation assays Molecular cell High 35216668
2004 Human RIF1 localizes to dysfunctional telomeres and DSB-induced foci in an ATM- and 53BP1-dependent manner (not dependent on ATR, BRCA1, Chk2, Nbs1, or Mre11). RIF1 inhibition results in radiosensitivity and defects in the intra-S-phase checkpoint, acting in a pathway distinct from Nbs1. Immunofluorescence foci analysis, siRNA knockdown, epistasis with checkpoint mutants Genes & development High 15342490
2018 53BP1-RIF1-shieldin counteracts DSB resection through CTC1-STN1-TEN1 (CST) complex, which interacts with shieldin and localizes with Polα to DSB sites in a 53BP1- and shieldin-dependent manner. CST-Polα-mediated fill-in of resected DNA helps control repair pathway choice, with CST acting downstream of RIF1. Co-immunoprecipitation, foci formation, RNAi knockdown, PARP inhibitor sensitivity assays Nature High 30022158
2012 RIF1 is a critical determinant of the replication timing program in human cells; depletion results in loss of mid-S replication foci profiles, stimulation of early-S initiation events, and changes in long-range replication timing domain structures. Rif1 binds nuclear-insoluble structures at late-M-to-early-G1 and colocalizes with mid-S replication foci, regulating chromatin-loop sizes. RNAi knockdown, BrdU incorporation/replication timing analysis, chromatin fractionation, immunofluorescence The EMBO journal High 22850673 22850674
2014 RIF1 controls DNA replication by directing Protein Phosphatase 1 (PP1) to reverse Cdc7/DDK-mediated phosphorylation of the MCM complex; PP1-interaction motifs (RVxF and SILK) within Rif1 N-terminal domain are critical for replication repression, and this repression is itself regulated by DDK phosphorylation near the PP1-interacting motifs. Genetic analysis, biochemical PP1 interaction assays, phosphorylation assays of Mcm4, co-IP, mutagenesis Genes & development High 24532715
2014 Budding yeast Rif1 inhibits prereplication complex (pre-RC) activation through PP1 (Glc7) recruitment via RVxF and SILK motifs; Glc7 interacts with Rif1 in G1 phase and Mcm4 and Sld3 show increased DDK phosphorylation in rif1 mutants. Rif1 also interacts with Dbf4 in two-hybrid assays. Yeast two-hybrid, co-IP, mutagenesis of PP1-docking motifs, replication timing analysis, phosphorylation assays Cell reports High 24656819 24685139
2017 Human RIF1-PP1 complex negatively regulates DNA replication by limiting phosphorylation-mediated activation of the MCM replicative helicase, specifically on MCM4 N-terminal domain. Additionally, RIF1-PP1 positively regulates origin licensing in G1 by protecting ORC1 from untimely phosphorylation and consequent proteasomal degradation. Mass spectrometry phosphoproteomics, RIF1 depletion, PP1 inhibition, protein stability assays, origin spacing analysis EMBO reports High 28077461
2017 Reversal of DDK-mediated MCM phosphorylation by Rif1-PP1 regulates replication initiation; hyperphosphorylation of DNA-bound Mcm4 correlates with DNA replication. Rif1 loss increases MCM phosphorylation and the rate of replication initiation and compromises the ability to block initiation upon replication stress. Rif1 can also mediate MCM dephosphorylation at replication forks. Xenopus egg extracts, human cell analysis, DDK inhibitors, phosphorylation assays Cell reports High 28273463
2017 Mouse Rif1 is a high-affinity PP1 adaptor; using NMR, isothermal calorimetry, surface plasmon resonance, and mutagenesis, Rif1 was shown to out-compete the PP1-inhibitor I2 in vitro, demonstrating it acts as a regulatory PP1-targeting subunit. NMR, isothermal calorimetry, surface plasmon resonance, mutagenesis, co-IP Scientific reports High 28522851
2015 Rif1 binds to G-quadruplex-like structures at specific intergenic regions in fission yeast, and this binding suppresses replication over long distances (up to 50 kb); base substitutions within G4-containing binding motifs abolish Rif1 binding and activate nearby late/dormant origins. ChIP-seq, in vitro G4 binding assays, mutagenesis, replication timing analysis Nature structural & molecular biology High 26436827
2015 Rif1 organizes nuclear architecture by coating late-replicating domains and restricting interactions between replication-timing domains during G1 phase; loss of Rif1 affects number and replication-timing specificity of domain interactions. During S phase, Rif1 ensures temporally coordinated replication of interacting domains. Hi-C/chromosome conformation capture, immunofluorescence, replication timing analysis, Lamin B1 co-localization Molecular cell High 26725008
2017 Rif1 N-terminal domain (Rif1-NTD) forms an α-helical fold shaped like a shepherd's crook and contains a high-affinity DNA-binding site that fully encases DNA as a head-to-tail dimer. Engagement of Rif1-NTD with telomeres is essential for checkpoint control and telomere length regulation, and Rif1-NTD also promotes NHEJ at DNA breaks in yeast. Crystal structure determination, DNA binding assays, in vivo functional assays, mutagenesis Nature structural & molecular biology High 28604726
2013 Crystal structures of yeast Rif1 and Rif2 bound to the Rap1 C-terminal domain reveal that both proteins have separable and independent Rap1-binding epitopes allowing binding over large distances. Rif1 contains a tetramerization module that, together with long-range Rap1 binding, creates a higher-order architecture that interlinks Rap1 units at telomeres. X-ray crystallography, biochemical analysis, functional in vivo assays Cell High 23746845
2009 Mammalian Rif1 accumulates at stalled replication forks, preferentially around pericentromeric heterochromatin, and RNAi against human Rif1 decreases efficiency of homology-directed repair (HDR). Rif1 deficiency affects S-phase progression and renders cells hypersensitive to replication poisons. Conditional mouse knockout, siRNA knockdown, HDR reporter assay, immunofluorescence at stalled forks The Journal of cell biology High 19948482
2010 Human Rif1 is a novel component of the BLM complex, physically interacting with it through a conserved C-terminal domain. Rif1 provides a DNA-binding interface for the BLM complex via a domain that preferentially binds fork and Holliday junction DNA in vitro, and is required for Rif1 to resist replication stress in vivo. Co-immunoprecipitation, in vitro DNA binding assays, genetic epistasis in DT40 cells, immunofluorescence The EMBO journal High 20711169
2019 RIF1-PP1 promotes replication fork protection by preventing DNA2-WRN-mediated over-degradation of nascent DNA at stalled replication forks. RIF1 limits phosphorylation of WRN at sites implicated in resection control. This function is independent of NHEJ but dependent on PP1 interaction. DNA fiber assay, nascent DNA degradation assays, co-IP, knockdown, mutagenesis Cell reports High 31141682
2019 RIF1 is enriched at stalled replication forks and protects reversed forks from DNA2 nuclease-mediated degradation; this function depends on PP1 interaction but is independent of NHEJ function. RIF1 deficiency delays fork restart and leads to exposure of under-replicated DNA. DNA fiber assay, proximity ligation assay, co-IP, siRNA knockdown Nature communications High 31337767
2019 RIF1-PP1 controls abscission timing by recruiting PP1 to the midbody, which counteracts Aurora B kinase activity and leads to dephosphorylation of CHMP4C. This cytokinetic function is not limited to instances of DNA bridge formation. Live-cell imaging, siRNA knockdown, Aurora B/PP1 activity assays, CHMP4C phosphorylation analysis Current biology : CB High 30905608
2015 Rif1 is recruited to ultrafine DNA bridges (UFBs) in anaphase in a PICH-dependent fashion, independently of 53BP1 or BLM. Rif1 promotes resolution of UFBs: its depletion increases frequency of nucleoplasmic bridges and RPA70-positive UFBs in late anaphase, and leads to more nuclear bodies with damaged DNA in G1. Immunofluorescence, siRNA knockdown, live-cell imaging, epistasis analysis Developmental cell High 26256213
2014 Rif1 in mouse embryonic stem cells negatively regulates Zscan4 expression by maintaining H3K9me3 levels at subtelomeric regions, thereby regulating telomere length homeostasis. Rif1 interacts with and stabilizes the H3K9 methylation complex. Co-immunoprecipitation, ChIP, shRNA knockdown, rescue experiments Developmental cell High 24735877
2017 Rif1 directly occupies endogenous retroviruses (ERVs) and is required for repressive histone marks H3K9me3 and H3K27me3 assembly and DNA methylation at ERV regions. Rif1 interacts with histone methyltransferases and facilitates their recruitment to ERV regions; the HEAT-like domain is essential for this function. ChIP-seq, ATAC-seq, co-immunoprecipitation, RNAi and gene deletion, methyltransferase recruitment assays Nucleic acids research High 29040764
2022 H3K4 methylation by SETD1A-BOD1L facilitates RIF1 recruitment to DSBs; RIF1 binds directly to methylated H3K4, enabling its recruitment to or stabilization at DSBs independently of, but cooperatively with, phospho-53BP1 interaction. Co-immunoprecipitation, ChIP, in vitro histone binding assays, SETD1A patient cell analysis, class switch recombination assay Molecular cell High 35439434
2022 RIF1 interacts with ASF1 histone chaperone in a manner similar to ASF1's interactions with CAF-1 and HIRA. ASF1 is recruited by 53BP1-RIF1 to chromatin flanking DSBs and promotes NHEJ through histone chaperone activity by compacting chromatin adjacent to breaks to prevent BRCA1-mediated resection. Co-immunoprecipitation, epistasis analysis, chromatin compaction assays, HR/NHEJ reporter assays Nature communications High 35177609
2023 AlphaFold2 predicted a novel direct binding interface between the HEAT-repeat domain of RIF1 and the eIF4E-like domain of SHLD3 (shieldin subunit). In vitro pulldown and cellular assays confirmed that RIF1-SHLD3 direct interaction is essential for shieldin recruitment to DSBs, antibody class switch recombination, and PARP inhibitor sensitivity. AlphaFold2 structural prediction, in vitro pulldown, cellular foci assays, class switch recombination, PARP inhibitor sensitivity assays EMBO reports High 37306046
2017 CSB (SWI2/SNF2 family chromatin remodeler) interacts via its winged helix domain with RIF1 and this interaction mediates CSB recruitment to DSBs in S phase. At DSBs, CSB evicts histones to limit RIF1/MAD2L2 accumulation and promote BRCA1 access. CSB chromatin remodeling requires ATM-dependent phosphorylation on S10 and CDK2-dependent phosphorylation on S158. Co-immunoprecipitation, domain mapping, ChIP, foci analysis, ATPase activity assays Nature communications High 29203878
2018 SCAI (suppressor of cancer cell invasion) binds 53BP1 phosphorylated at S/TP sites and inhibits RIF1 function. Upon DNA damage, RIF1 accumulates at damage sites first and then is replaced by SCAI, allowing BRCA1-mediated repair. Co-immunoprecipitation, foci kinetics assays, HR reporter assay, siRNA knockdown Cell reports Medium 28700933
2018 H4K20me2 distinguishes pre-replicative from post-replicative chromatin to direct DSB repair pathway choice; MAD2L2 is recruited to DSBs in H4K20me2 chromatin by forming a protein complex with 53BP1 and RIF1. Replication-associated dilution of H4K20me2 reduces 53BP1-RIF1-MAD2L2 complex recruitment, allowing BRCA1 access. Co-immunoprecipitation, foci analysis, cell cycle-resolved ChIP, replication-coupled chromatin analysis Cell cycle (Georgetown, Tex.) Medium 29160738
2014 Murine Rif1 C-terminal conserved region II (CRII) binds cruciform DNA with high selectivity and micromolar affinity as shown by NMR; a specific α-helical region of CRII with critical residues identified by mutagenesis is required for cruciform DNA binding. NMR analysis, ESPRIT protein evolution, in vitro DNA binding assays, mutagenesis The Journal of biological chemistry High 24634216
2018 Purified murine Rif1 forms elongated homo-oligomers and binds G-quadruplex (G4) DNA with high specificity and affinity. Both N-terminal (HEAT-repeat) and C-terminal segments are involved in oligomer formation and G4 binding; the central intrinsically disordered segment increases affinity for G4. Pulldown assays show Rif1 can simultaneously bind multiple G4 molecules. Protein purification, hydrodynamic analysis, G4 binding assays, pulldown The Journal of biological chemistry High 29348174
2019 Yeast Rif1 is S-acylated within its conserved N-terminal domain at cysteine residues C466 and C473 by the DHHC palmitoyl acyltransferase Pfa4. This S-acylation facilitates Rif1 accumulation at DSBs at the inner nuclear membrane, DNA end-resection attenuation, and DSB repair by NHEJ. Mass spectrometry-based acylation detection, mutagenesis, Pfa4 knockout, DSB repair assays, NHEJ assays Nature communications High 31182712
2009 In budding yeast, Rif1 and Rif2 inhibit Tel1 (ATM homolog) recruitment to DNA ends through distinct mechanisms; Rif2 competes with Tel1 for binding to the C terminus of Xrs2, while Rif1 inhibition is weaker at short telomeric repeats and partly dependent on Rif2. ChIP, genetic epistasis, telomere binding assays, two-hybrid Molecular cell High 19217405
2011 In budding yeast, Rif1 is palmitoylated by Pfa4, and acylated Rif1 anchors to the inner nuclear membrane. Loss of palmitoylation disperses Rif1-GFP from nuclear peripheral foci and disrupts Sir3-GFP distribution, affecting heterochromatin dynamics at HM loci. Acylation detection assays, GFP imaging, genetic epistasis, Pfa4 knockout Proceedings of the National Academy of Sciences of the United States of America High 21844336
2018 RIF1 promotes Wnt/β-catenin signaling in NSCLC by directing PP1 to dephosphorylate AXIN, promoting β-catenin nuclear activity. RIF1 overexpression promotes PP1-AXIN interaction, and PP1 inhibition counteracts RIF1's effects on cell growth and Wnt signaling. Co-immunoprecipitation, phosphorylation assays, PP1 inhibition, reporter assays, xenograft Cell death & disease Medium 30237512
2013 In budding yeast, Rif1 inhibits resection and cooperates with the CST complex for telomere capping; loss of Rif1 is lethal in stn1ΔC cells and causes severe defects in cdc13 mutants, with accumulation of telomeric single-stranded DNA and checkpoint activation. This synthetic interaction is partially rescued by deletion of Exo1 nuclease. Genetic epistasis, viability assays, checkpoint activation analysis, ssDNA detection PLoS genetics Medium 21437267
2018 In Drosophila, Cdk1 activity inhibits chromatin association of Rif1 at the mid-blastula transition; following Cdk1 downregulation, Rif1 binds selectively to satellite sequences and dissociates in an orderly schedule anticipating their replication. A phosphorylation-site mutant Rif1 fails to dissociate and dominantly prevents completion of replication. Live imaging, immunostaining, mutant analysis, genetic rescue experiments PLoS biology High 29746464
2018 In Drosophila polyploid cells, Rif1 interacts with the SUUR protein, localizes to active replication forks in a partially SUUR-dependent manner, and directly regulates replication fork progression to promote DNA underreplication. SUUR associates with forks in the absence of Rif1, placing Rif1 downstream of SUUR. Co-immunoprecipitation, DNA copy number analysis, immunofluorescence at forks, genetic epistasis eLife High 30277458
2014 In budding yeast, Tel1 kinase directs early replication of short telomeres by counteracting Rif1-mediated replication delay. Tel1 phosphorylates Rif1 at S/TQ sites (including Serine-1308) in cells with short telomeres, as shown by proteomic analysis. Replication timing analysis, proteomics, phosphomutant analysis, genetic epistasis PLoS genetics Medium 25329891
2012 Rif1 is a global regulator of replication origin firing in fission yeast; extensive deregulation of dormant origins occurs in rif1Δ. Rif1 binds not only to telomeres but also to many specific locations on chromosome arms near late/dormant origins from M to G1 phase, independent of Taz1, and this binding is essential for the replication timing program. ChIP, genome-wide replication analysis, genetic analysis, cell cycle fractionation Genes & development High 22279046

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 A cell cycle-dependent regulatory circuit composed of 53BP1-RIF1 and BRCA1-CtIP controls DNA repair pathway choice. Molecular cell 740 23333306
2013 RIF1 is essential for 53BP1-dependent nonhomologous end joining and suppression of DNA double-strand break resection. Molecular cell 518 23333305
2013 53BP1 regulates DSB repair using Rif1 to control 5' end resection. Science (New York, N.Y.) 502 23306437
1980 A new mouse tumor model system (RIF-1) for comparison of end-point studies. Journal of the National Cancer Institute 430 6928244
2018 53BP1-RIF1-shieldin counteracts DSB resection through CST- and Polα-dependent fill-in. Nature 350 30022158
2013 Rif1 prevents resection of DNA breaks and promotes immunoglobulin class switching. Science (New York, N.Y.) 339 23306439
2013 RIF1 counteracts BRCA1-mediated end resection during DNA repair. The Journal of biological chemistry 229 23486525
2012 Rif1 regulates the replication timing domains on the human genome. The EMBO journal 200 22850674
2012 Rif1 is a global regulator of timing of replication origin firing in fission yeast. Genes & development 197 22279046
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