Affinage

MRE11

Double-strand break repair protein MRE11 · UniProt P49959

Length
708 aa
Mass
80.6 kDa
Annotated
2026-04-28
100 papers in source corpus 56 papers cited in narrative 56 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MRE11 is the catalytic nuclease subunit of the conserved MRE11–RAD50–NBS1 (MRN) complex and serves as a central organizer of the DNA double-strand break response, coupling DNA end processing to checkpoint signaling, repair pathway choice, telomere maintenance, replication fork stability, and innate immune activation. As a bifunctional nuclease, MRE11 uses ATP-dependent conformational switching of RAD50 to alternate between endonuclease and 3′→5′ exonuclease activities: ATP binding closes RAD50, licensing endonucleolytic nicking of the 5′ strand internal to a break, while ATP hydrolysis opens the complex to permit bidirectional exonucleolytic resection toward the DNA end, thereby initiating homologous recombination and removing protein adducts including Ku and Spo11 (PMID:24316220, PMID:22102415, PMID:22002605, PMID:27814491, PMID:31492634). MRN directly activates ATM kinase through a two-step mechanism—DNA tethering increases local ATM concentration and the Nbs1 C-terminal domain then converts ATM monomers to active monomers—while MRE11-dependent resection also generates ssDNA required for ATR activation (PMID:15064416, PMID:16622404, PMID:15509802). MRE11 activity is tuned by a dense network of post-translational modifications—including PRMT1-mediated arginine methylation, UFMylation at K282, lactylation at K673 by CBP, SUMOylation by PIAS1, ubiquitination by RNF126, and Plk1/CK2 phosphorylation—and by regulatory partners such as DYNLL1 (which disrupts the MRE11 dimer to limit resection), METTL16, CtIP, and p97/VCP, integrating MRE11 nuclease output with cell-cycle state, chromatin context, and repair pathway balance including its roles at stalled replication forks, uncapped telomeres, and in mobilizing cGAS from nucleosome sequestration to activate innate immune signaling (PMID:18285453, PMID:30783677, PMID:38128537, PMID:36050397, PMID:30464262, PMID:36138131, PMID:38200309).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1999 High

    Establishing the enzymatic activities of the trimeric complex: NBS1 was shown to potentiate ATP-driven DNA unwinding and switch MRE11 endonuclease specificity, defining the MRN complex as a regulated nuclease machine rather than a simple exonuclease.

    Evidence In vitro reconstitution with purified human Nbs1, Mre11, and Rad50; Rad50 ATP-binding mutants

    PMID:10346816

    Open questions at the time
    • Human NBS1-dependent activities not yet confirmed structurally
    • Physiological substrates of endonuclease activity undefined
  2. 2000 High

    MRN was placed at telomeres through cell-cycle-regulated association with TRF2, revealing a constitutive role beyond acute DSB repair and linking the complex to chromosome end protection.

    Evidence Mass spectrometry of TRF2 immunocomplexes; immunofluorescence and cell-cycle synchronization in human cells

    PMID:10888888

    Open questions at the time
    • Functional consequence of MRN–TRF2 interaction for telomere processing not yet defined
    • Mechanism of cell-cycle regulation of NBS1 telomere association unknown
  3. 2001 High

    Two parallel discoveries established MRE11's roles beyond DSB processing: it prevents DSB accumulation during replication (replication fork stability function) and promotes NHEJ by tethering DNA ends and stimulating DNA ligase IV–mediated ligation.

    Evidence Xenopus egg extract immunodepletion and replication assays; in vitro intermolecular ligation with purified yeast MRX and Dnl4/Lif1

    PMID:11511367 PMID:11741545

    Open questions at the time
    • Molecular mechanism of MRE11 fork protection unknown
    • Whether MRN DNA tethering for NHEJ uses the same conformational states as for HR resection was untested
  4. 2004 High

    MRN was established as a direct activator of ATM kinase, and MRE11's C-terminal domain was shown to scaffold ATM–DNA signaling complexes, connecting MRE11 enzymatic activities to checkpoint signaling and explaining ATLD disease pathology.

    Evidence In vitro ATM kinase reconstitution with purified MRN; Xenopus egg extract size-exclusion chromatography with ATLD truncation mutants; genetic epistasis in yeast placing MRX upstream of Mec1 via ssDNA generation

    PMID:15064416 PMID:15138496 PMID:15234984 PMID:15509802

    Open questions at the time
    • Two-step activation mechanism not yet dissected
    • How MRN coordinates simultaneous ATM and ATR activation in vivo unclear
  5. 2006 High

    A two-step model for ATM activation by MRN was established: MRN first tethers DNA to concentrate ATM monomers, then NBS1 directly converts inactive monomers to active kinase, separating the tethering and catalytic activation functions.

    Evidence Xenopus egg extracts with DNA titration to bypass MRN requirement; NBS1 domain-specific constructs

    PMID:16622404

    Open questions at the time
    • Structural basis for NBS1-mediated ATM monomer activation unknown
    • Whether this two-step model operates identically in mammalian cells untested
  6. 2007 High

    Rad50 was found to possess adenylate kinase activity in addition to ATPase activity, and this kinase function was specifically required for DNA tethering, revealing an additional enzymatic contribution to MRN function.

    Evidence In vitro adenylate kinase assays; adenylate kinase inhibitor blocks tethering in Xenopus extracts; yeast genetics phenocopies rad50Δ

    PMID:17349953

    Open questions at the time
    • Physiological relevance of adenylate kinase vs. ATPase activity not fully separated in vivo
    • Whether human Rad50 retains this activity unconfirmed
  7. 2008 High

    Two parallel advances defined MRE11 regulation and structure: PRMT1-mediated arginine methylation at the GAR motif was shown to regulate MRE11 nuclease activity and DNA binding, while crystal structures revealed the MRE11 dimer architecture critical for DNA end alignment.

    Evidence In vitro methylation and nuclease assays; crystal structure and SAXS of P. furiosus Mre11 dimer; fission yeast mutagenesis

    PMID:18285453 PMID:18854158

    Open questions at the time
    • Which arginines are methylated in vivo under physiological conditions unknown
    • How dimer architecture coordinates with Rad50 conformational changes unresolved
  8. 2009 High

    Conditional mouse genetics definitively separated MRE11's nuclease-dependent and nuclease-independent roles at telomeres: MRE11 nuclease removes 3′ overhangs enabling NHEJ fusions after TRF2 loss and generates 3′ overhangs at leading-strand telomeres, while the complex is required for ATM activation at deprotected ends.

    Evidence Conditional Mre11 knockout and nuclease-dead alleles in mouse; TRF2 cre-mediated deletion; telomere FISH and cytogenetics

    PMID:19633651

    Open questions at the time
    • How MRE11 nuclease is directed to process leading vs. lagging telomeres differently not established
  9. 2011 High

    Multiple studies converged to define MRE11's bidirectional resection mechanism and its regulation: endonucleolytic nicking ~300 nt from the break licenses 5′→3′ Exo1 resection and 3′→5′ MRE11 exonuclease resection toward the break, while ATP hydrolysis acts as a molecular switch between endo- and exonuclease modes, and arginine methylation controls exonuclease/resection efficiency in vivo.

    Evidence Meiotic resection assays in yeast with nuclease mutants; biochemical endo/exo nuclease switching with ATP analogs; Mre11 RK/RK knock-in mice with ATR signaling and resection readouts; MMEJ reporter assays

    PMID:20647759 PMID:21826105 PMID:22002605 PMID:22102415

    Open questions at the time
    • How Mre11 endonuclease positions its nick relative to the break end mechanistically unclear
    • Regulation of endo-to-exo switch by cofactors in vivo not resolved
  10. 2013 High

    Structure-based inhibitors separating MRE11 endo- from exonuclease activities demonstrated that endonuclease initiates resection to license HR (its inhibition shifts repair to NHEJ), while single-molecule FRET showed MRN unwinds 15–20 bp at DNA ends in an ATP-dependent manner, providing the initial substrate for nuclease action.

    Evidence Structure-guided inhibitor design with repair pathway choice assays; single-molecule FRET with Rad50 catalytic mutant validated in human cells

    PMID:24191051 PMID:24316220

    Open questions at the time
    • How MRN end-unwinding coordinates with CtIP in cells not defined
    • Whether inhibitors have off-target effects in long-term assays not excluded
  11. 2016 High

    The role of NBS1/Xrs2 was refined: Xrs2 is dispensable for MR nuclease activities and serves primarily as a nuclear import chaperone and ATM/NHEJ adaptor, while human NBS1 inhibits exonuclease on clean ends but licenses endonucleolytic cleavage on protein-blocked ends together with phosphorylated CtIP. Separately, cyclin A2 was found to regulate MRE11 protein levels through mRNA binding and translational control.

    Evidence Mre11-NLS rescue in xrs2Δ yeast with reconstituted MR nuclease assays; hMRN nuclease assays on protein-blocked substrates; cyclin A2 RNA immunoprecipitation, polysome fractionation, and conditional mouse mutants

    PMID:27708105 PMID:27746018 PMID:27814491

    Open questions at the time
    • Human NBS1 dispensability for nuclease activity not tested in vivo
    • Whether CtIP phosphorylation state determines endo vs. exo switch unknown
  12. 2017 High

    Single-molecule imaging showed MRN uses facilitated diffusion on nucleosome-coated DNA to locate free ends, with Rad50 driving the search and Mre11 recognizing and removing Ku from ends; Plk1/CK2 dual phosphorylation was identified as a negative regulatory mechanism terminating MRN loading on damaged chromatin; and MRE11/EXO1 were shown to degrade reversed forks in BRCA2-deficient cells via a CtIP-initiated pathway.

    Evidence Single-molecule microscopy with domain mutants; in vitro kinase assays with phosphomimetic mutants; DNA fiber and EM of replication forks in BRCA2-deficient cells

    PMID:28512243 PMID:28867292 PMID:29038425

    Open questions at the time
    • How Mre11 discriminates Ku-blocked from clean ends during diffusion unknown
    • Whether Plk1-CK2 phosphorylation operates at replication forks in addition to DSBs untested
  13. 2018 High

    DYNLL1 was identified as a direct negative regulator of MRE11 end resection: its loss restores HR in BRCA1-mutant cells, and GFI1 was shown to be a cofactor enabling PRMT1-mediated MRE11 methylation, extending the regulatory network controlling MRE11 nuclease output.

    Evidence CRISPR screen and in vitro binding for DYNLL1-MRE11; co-IP and in vitro methylation assay for GFI1-PRMT1-MRE11

    PMID:29651020 PMID:30464262

    Open questions at the time
    • Structural mechanism by which DYNLL1 inhibits MRE11 not yet resolved
    • Whether GFI1 is required for MRE11 methylation outside T cells unknown
  14. 2019 High

    The ATP-bound closed conformation of MR was shown essential for ATM activation via separation-of-function alleles, and MRE11 UFMylation at K282 was identified as required for MRN complex formation, ATM activation, and HR repair; cryo-EM structures of bacterial MR captured resting and DNA-cutting states, revealing how Rad50 autoinhibits and then repositions Mre11 into a cutting channel.

    Evidence S. cerevisiae separation-of-function alleles with Tel1 ChIP and MD simulations; MS identification of UFMylation site with functional assays; cryo-EM of E. coli SbcCD in multiple states

    PMID:30698745 PMID:30783677 PMID:31492634

    Open questions at the time
    • Whether UFMylation regulates the closed-to-open conformational switch unknown
    • Human cryo-EM structure of MRN still lacking
  15. 2021 High

    UFMylation was linked to telomere maintenance through PP1-α-mediated NBS1 dephosphorylation controlling MRN telomere recruitment; PARP14 mono-ADP-ribosylation was found to facilitate MRE11 engagement at stalled forks; and loss of MRE11's ATLD domain was connected to PARP-dependent protein aggregation relevant to A-T neuropathology.

    Evidence Zebrafish and HeLa UFMylation-deficient models with telomere assays; iPOND and fiber assays for PARP14-MRE11 at forks; insoluble protein fractionation and A-T patient cerebellum analysis

    PMID:33571423 PMID:34559557 PMID:36030235

    Open questions at the time
    • Whether PARP14-mediated ADP-ribosylation and UFMylation crosstalk at forks is unknown
    • Protein aggregation mechanism in ATLD needs reconstitution
  16. 2022 High

    A wave of structural, regulatory, and functional discoveries in 2022 defined: eukaryotic MRN cryo-EM architecture (2:2:1 stoichiometry with 120-nm tethering via zinc hooks); substrate-specific structural mechanisms for endonucleolytic cleavage of blocked ends; Rad50-mediated oligomerization driving multi-site endonucleolytic cleavage; and multiple new PTM regulatory axes—SUMOylation by PIAS1 protecting MRE11 from degradation, RNF126 ubiquitination activating exonuclease, and METTL16-RNA-mediated inhibition released by ATM phosphorylation.

    Evidence Cryo-EM of C. thermophilum MRN and bacterial SbcCD with blocked substrates; EM and genetics of Rad50-mediated oligomerization; biochemical SUMOylation, ubiquitination, and exonuclease assays with writer/eraser identification

    PMID:35501303 PMID:35987200 PMID:36050397 PMID:36138131 PMID:36563124 PMID:36577401

    Open questions at the time
    • Human MRN cryo-EM structure at high resolution not yet available
    • How oligomeric assemblies integrate with nucleosome-coated chromatin in vivo is unclear
    • Interplay among SUMOylation, ubiquitination, and methylation on the same MRE11 molecule unknown
  17. 2023 High

    Lactylation at K673 by CBP (downstream of ATM-dependent CBP phosphorylation) was identified as a damage-induced modification promoting MRE11 DNA binding and resection; DYNLL1 was shown to inhibit MRE11 by disrupting its dimer interface and regulating Shieldin recruitment; and MRE11 was placed in bidirectional gap expansion leading to DSB generation at replication stress-induced ssDNA gaps.

    Evidence Mass spectrometry, CBP acetyltransferase assays, and patient-derived xenograft models for lactylation; structural analysis of DYNLL1-MRE11 dimer disruption with Shieldin epistasis; fiber and gap assays with MRE11/EXO1 inhibition in BRCA-deficient cells

    PMID:37696958 PMID:37805499 PMID:38128537

    Open questions at the time
    • Whether lactylation and methylation at the GAR motif are mutually exclusive unknown
    • How DYNLL1-mediated dimer disruption is reversed to re-enable resection unclear
    • Whether gap-to-DSB conversion is a physiological repair pathway or purely pathological in BRCA-deficient context unknown
  18. 2024 High

    MRN was shown to activate innate immunity by displacing cGAS from nucleosome sequestration: MRE11 binds nucleosome fragments at their acidic patch, releasing cGAS for activation by dsDNA, connecting MRE11 to ZBP1-RIPK3-MLKL necroptosis and tumor suppression.

    Evidence Biochemical MRN-nucleosome binding and cGAS displacement assays; genetic MRE11 depletion; necroptosis pathway epistasis; mouse mammary tumor models

    PMID:38200309

    Open questions at the time
    • Whether MRE11 nuclease activity is required for cGAS mobilization or only physical binding suffices unknown
    • How MRE11 encounters cytosolic nucleosomes (vs. nuclear chromatin) not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include: the high-resolution cryo-EM structure of intact human MRN on physiological chromatin substrates; how the multiple PTMs (methylation, UFMylation, lactylation, SUMOylation, ubiquitination, ADP-ribosylation, phosphorylation) are coordinated on the same MRE11 molecule; the structural basis for DYNLL1-mediated dimer disruption and its reversal; and how MRE11's nuclear DSB repair and cytoplasmic innate immune functions are spatially and temporally segregated.
  • No high-resolution structure of human MRN on nucleosomal DNA
  • PTM crosstalk hierarchy unresolved
  • Spatial regulation of nuclear vs. cytoplasmic MRE11 functions unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140097 catalytic activity, acting on DNA 11 GO:0140096 catalytic activity, acting on a protein 8 GO:0003677 DNA binding 5 GO:0140657 ATP-dependent activity 4
Localization
GO:0005634 nucleus 6 GO:0005694 chromosome 4 GO:0005654 nucleoplasm 1 GO:0005739 mitochondrion 1
Pathway
R-HSA-73894 DNA Repair 9 R-HSA-162582 Signal Transduction 6 R-HSA-69306 DNA Replication 5 R-HSA-1640170 Cell Cycle 4 R-HSA-168256 Immune System 2 R-HSA-5357801 Programmed Cell Death 1
Partners
CTIPDYNLL1EXO1GRB2NBS1PRMT1RAD50TRF2
Complex memberships
MRN complex (MRE11-RAD50-NBS1)

Evidence

Reading pass · 56 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 The MRN complex (Mre11/Rad50/Nbs1) directly stimulates ATM kinase activity in vitro toward substrates p53, Chk2, and histone H2AX; MRN makes multiple contacts with ATM and facilitates stable substrate binding; phosphorylation of Nbs1 is critical for MRN stimulation of ATM toward Chk2 but not p53. In vitro kinase reconstitution with purified recombinant MRN and ATM; substrate phosphorylation assays; kinase-deficient ATM dominant-negative analysis Science High 15064416
1999 Nbs1 potentiates ATP-driven DNA unwinding and endonuclease cleavage activities of the Mre11/Rad50 complex; the triple complex displays partial duplex unwinding and efficient hairpin cleavage not seen without Nbs1; ATP controls a switch in endonuclease specificity allowing cleavage of 3'-protruding strands; Rad50 is responsible for ATP binding. In vitro biochemical assays with recombinant Nbs1, Mre11, and Rad50; mutational analysis of Rad50 ATP-binding domain Genes & development High 10346816
2000 RAD50, MRE11, and NBS1 associate with TRF2 at human telomeres in a cell-cycle-regulated manner; NBS1 associates with TRF2 and telomeres specifically in S phase but not G1 or G2, while RAD50 and MRE11 localize to interphase telomeres throughout the cell cycle. Nanoelectrospray tandem mass spectrometry of TRF2 immunocomplexes; protein blotting; indirect immunofluorescence; cell-cycle synchronization Nature genetics High 10888888
2013 MRE11 endonuclease activity initiates DNA end resection licensing homologous recombination (HR), while MRE11 exonuclease activity is required for bidirectional resection toward the DNA end following endonucleolytic nick; endonuclease inhibition promotes NHEJ in lieu of HR, whereas exonuclease inhibition confers a repair defect. Structure-based design of specific endo- vs. exonuclease inhibitors; RPA chromatin binding assays; repair pathway choice analysis after G2 DSBs induced by radiation; chemical library screening Molecular cell High 24316220
2008 Mre11 forms a dimer that adopts a four-lobed U-shaped structure critical for MRN complex assembly and DNA end binding/alignment; Mre11 endonuclease activity is required for cell survival after DSB induction but not for MRN complex assembly or Ctp1 recruitment to DSBs. Small-angle X-ray scattering (SAXS) and crystal structures of Pyrococcus furiosus Mre11 dimer bound to DNA; mutational analyses in fission yeast Mre11 Cell High 18854158
2011 Mre11 endonuclease activity nicks the 5'-strand up to ~300 nt from the DSB end, enabling bidirectional resection: Exo1 resects 5'→3' away from the break and Mre11 exonuclease resects 3'→5' toward the DSB end to remove Spo11-linked termini in meiosis. Physical assays for 5'-end processing in S. cerevisiae; in vivo meiotic resection analysis using nuclease-deficient and Exo1 mutant strains Nature High 22002605
2023 MRE11 is lactylated at K673 by the CBP acetyltransferase in response to DNA damage; this lactylation depends on ATM phosphorylation of CBP; MRE11 lactylation promotes its DNA binding, DNA end resection, and HR repair. Mass spectrometry identification of lactylation site; CBP acetyltransferase assay; LDH inhibition; cell-penetrating peptide blocking MRE11 K673 lactylation; patient-derived xenograft and organoid models Cell High 38128537
2010 MRX (Mre11-Rad50-Xrs2) and Sae2 promote 5'-strand resection by stimulating Exo1 through cooperative DNA substrate binding; MRX and Sae2 stimulate Exo1-catalyzed 5'-strand degradation when Exo1 levels are limiting. In vitro reconstitution with purified MRX, Sae2, and Exo1; exonuclease assays on defined DNA substrates Nature structural & molecular biology High 21102445
2016 Human Mre11/Rad50/Nbs1 (hMRN) catalyzes sequential endonucleolytic and exonucleolytic cleavage on both 5' and 3' strands at DNA ends containing protein adducts; Nbs1, ATP, and protein adducts are essential for this activity; Nbs1 inhibits Mre11/Rad50-catalyzed 3'→5' exonuclease on clean DNA ends; phosphorylated CtIP further stimulates endonucleolytic cleavage. In vitro nuclease assays with purified hMRN; defined protein-blocked DNA substrates; mutational analysis; CtIP phosphorylation stimulation assay Molecular cell High 27814491
2017 MRN searches for free DNA ends by one-dimensional facilitated diffusion on nucleosome-coated DNA; Rad50 binds homoduplex DNA to promote diffusion; Mre11 is required for DNA end recognition and nuclease activities; MRN removes Ku from DNA ends via Mre11-dependent nucleolysis; MRN acts as a processivity factor for Exo1 in the presence of RPA for long-range resection. High-throughput single-molecule microscopy; nucleosome-coated DNA substrates; domain-specific mutants; direct visualization of protein-DNA interactions Molecular cell High 28867292
2001 Xenopus Mre11 complex is required to prevent accumulation of double-strand breaks during chromosomal DNA replication; immunodepletion of X-Mre11 complex from Xenopus egg extracts results in DSB accumulation in replicated DNA; DSBs stimulate phosphorylation and 3'→5' exonuclease activity of X-Mre11; the ATM-dependent replication checkpoint is Mre11-independent. Xenopus egg extract cell-free replication system; immunodepletion; TUNEL assay; γH2AX detection; exonuclease activity assays Molecular cell High 11511367
2001 The Rad50/Mre11/Xrs2 complex juxtaposes linear DNA molecules via their ends to form oligomers, interacts directly with DNA ligase IV (Dnl4)/Lif1, and promotes intermolecular DNA ligation; this NHEJ-promoting function is further stimulated by the Ku70/Ku80 homolog Hdf1/Hdf2. In vitro intermolecular DNA joining assays; direct protein-protein interaction studies; purified recombinant yeast proteins Molecular cell High 11741545
2004 Mre11 assembles linear DNA fragments and activated ATM into high molecular weight DNA damage signaling complexes; complex formation requires an intact Mre11 C-terminal domain (deleted in ATLD patients); MRN is required for efficient activation of the DNA damage response at DSBs. Xenopus egg extract biochemistry; size exclusion chromatography; immunoprecipitation; ATLD truncation mutant analysis PLoS biology High 15138496
2006 ATM activation by DSBs occurs in two steps: MRN facilitates ATM monomerization by tethering DNA (increasing local concentration), then the ATM-binding domain of Nbs1 converts unphosphorylated ATM monomers into enzymatically active monomers independently of DNA. Xenopus egg extracts; titration of damaged DNA concentrations to bypass MRN requirement; domain-specific Nbs1 constructs; ATM phosphorylation assays Nature structural & molecular biology High 16622404
2011 ATP binding to Rad50 induces a closed conformation converting Mre11 into an endonuclease; ATP hydrolysis opens the Rad50-Mre11 complex and Mre11 maintains exonuclease activity; thus ATP hydrolysis acts as a molecular switch converting MRE11 from endonuclease to exonuclease. Biochemical nuclease assays; solution structural analysis showing open/closed conformational states upon nucleotide binding/hydrolysis The Journal of biological chemistry High 22102415
2019 Cryo-EM structures of bacterial Mre11-Rad50 (SbcCD) in resting and DNA-bound states reveal that: in the resting state, Mre11 nuclease is blocked by ATP-Rad50; upon DNA binding, Rad50 coiled coils zip into a rod forming a clamp around dsDNA; Mre11 moves to the side of Rad50 binding the DNA end and assembles a DNA cutting channel. Cryo-EM structural determination in resting and DNA-bound cutting states Molecular cell High 31492634
2022 Cryo-EM structure of eukaryotic Mre11-Rad50-Nbs1 (MRN from Chaetomium thermophilum) reveals a 2:2:1 complex with a single Nbs1 wrapping around an autoinhibited Mre11 dimer; MRN has two DNA-binding modes (ATP-dependent for loading onto DNA ends; ATP-independent through Mre11's C terminus); two 60-nm coiled-coil domains form a linear rod, and zinc-hook motifs allow MRN-MRN dimerization creating 120-nm spanning structures. Cryo-EM structural determination of eukaryotic MRN complex Molecular cell High 36577401
2022 Cryo-EM structures of bacterial SbcCD (Mre11-Rad50) bound to protein-blocked DNA ends and DNA hairpins show that Mre11-Rad50 bends internal DNA for endonucleolytic cleavage and processes blocked ends with Mre11 pointing away from the block, explaining the distinct biochemistries of 3'→5' exonuclease versus endonucleolytic incision. Cryo-EM structural determination with protein-blocked DNA end and hairpin substrates Molecular cell High 35987200
2018 DYNLL1 directly binds MRE11 to limit its end-resection activity; loss of DYNLL1 restores DNA end resection and HR in BRCA1-mutant cells; DYNLL1 limits nucleolytic degradation of DNA ends by associating with the MRN complex, BLM helicase, and DNA2. CRISPR loss-of-function screen; in vitro direct binding assay (DYNLL1 binds MRE11); HR assays in BRCA1-mutant cells; resection assays Nature High 30464262
2023 DYNLL1 is recruited to DSBs by 53BP1, where it limits end resection by binding and disrupting the MRE11 dimer; Shieldin complex recruitment to DSBs depends on MRE11 activity and is regulated by the DYNLL1-MRE11 interaction; constitutive DYNLL1-MRE11 association resensitizes BRCA1-deficient/Shieldin-loss cells to PARP inhibitors. Co-immunoprecipitation; structural analysis of DYNLL1-MRE11 dimer disruption; resection assays; PARP inhibitor sensitivity assays; epistasis with Shieldin Nature structural & molecular biology High 37696958
2019 MRE11 is UFMylated at K282 by the UFM1 pathway; this modification is required for MRN complex formation under unperturbed conditions and for DSB-induced optimal ATM activation and HR-mediated repair; a pathogenic cancer mutation MRE11(G285C) phenocopies the UFMylation-defective K282R mutant. Mass spectrometry identification of UFMylation site; UFMylation-defective mutant (K282R) analysis; ATM activation assays; HR repair assays; cancer mutation comparison Nucleic acids research High 30783677
2021 MRE11 UFMylation is necessary for recruitment of phosphatase PP1-α to dephosphorylate NBS1; without UFMylation, NBS1 remains phosphorylated, reducing MRN recruitment to telomeres; absence of MRN at telomeres favors TRF2-Apollo/SNM1 complex formation and loss of leading-strand telomeres. Zebrafish genetic models deficient in Ufm1 and Ufl1; HeLa cells lacking UFL1; telomere length assays; co-IP for PP1-α and NBS1 phosphorylation status; zebrafish expressing UFMylation-deficient Mre11 phenocopy Science advances High 34559557
2008 PRMT1 methylates MRE11 at the glycine-arginine-rich (GAR) motif; PRMT1 interacts with MRE11 but not the MRN complex, suggesting methylation precedes RAD50/NBS1 binding; the first six methylated arginines regulate MRE11 DNA binding and nuclease activity; methylation-deficient MRE11 shows reduced focus formation at DSBs. In vitro methylation assay in insect cells; co-immunoprecipitation; nuclease activity assays; live-cell imaging of DSB foci with laser microirradiation Molecular and cellular biology High 18285453
2011 Arginine methylation of MRE11 at the GAR motif by PRMT1 regulates DNA exonuclease activity and DNA end resection; Mre11(RK/RK) knock-in mice (arginines replaced by lysines) are hypersensitive to γ-irradiation, show ATR/CHK1 signaling defects, impaired RPA and RAD51 recruitment, while ATM signaling remains intact; the M(RK)RN complex has exonuclease and DNA-binding defects in vitro. Mouse knock-in model; in vitro exonuclease assays; cell cycle checkpoint analysis; immunofluorescence of RPA/RAD51 foci; western blotting for signaling Cell research High 21826105
2004 Nuclear Mre11-Rad50 (but not Nbs1) stimulates ATM activation at early times after low-dose radiation; both Mre11-Rad50 and Nbs1 independently serve as adaptors for some downstream ATM phosphorylation events (e.g., Smc1 at Ser-957 remains MRN-dependent even after Atm is active). Isogenic cell lines with nuclear depletion of either Nbs1 or Mre11-Rad50 using C-terminal Nbs1 nuclear localization; ATM autophosphorylation, Chk2, Nbs1, and Smc1 phosphorylation assays at different timepoints/doses The Journal of biological chemistry High 15234984
2017 Polo-like kinase 1 (Plk1) phosphorylates Mre11 at serine 649 during DNA damage response; this primes subsequent CK2-mediated phosphorylation at serine 688; dual phosphorylation at S649/S688 inhibits MRN complex loading onto damaged DNA, causing premature checkpoint termination and inhibition of DSB repair. In vitro kinase assay; phosphomimetic and unphosphorylatable Mre11 mutants; MRN foci assays; colony-forming assays; PARP inhibitor sensitivity Cancer research High 28512243
2013 MRN unwinds 15–20 base pairs at the end of a DNA duplex in an ATP-dependent reaction, holding the branched structure open for minutes; a Rad50 catalytic domain mutant specifically deficient in this ATP-dependent opening is impaired in DNA end resection in vitro and in resection-dependent DSB repair in human cells. Single-molecule FRET; Rad50 catalytic mutant analysis; in vitro resection assays; human cell DSB repair assays Proceedings of the National Academy of Sciences of the United States of America High 24191051
2019 The ATP-bound 'closed' conformation of the Mre11-Rad50 (MR) complex is essential for Tel1/ATM activation; separation-of-function alleles mre11-S499P and rad50-A78T specifically impair Tel1 activation without affecting DSB repair; Mre11-S499P reduces Mre11-Rad50 interaction; Rad50-A78T destabilizes the ATP-bound closed state as shown by molecular dynamics simulations. Genetic separation-of-function alleles in S. cerevisiae; Tel1 ChIP at DSBs; molecular dynamics simulations of MR conformational states Nucleic acids research High 30698745
2017 MRE11 and EXO1 nucleases degrade reversed replication forks in BRCA2-deficient cells; CtIP initiates MRE11-dependent degradation of regressed fork arms, which is extended by EXO1; initial limited resection of regressed arms establishes the substrate for MUS81, whose cleavage promotes POLD3-dependent fork rescue. DNA fiber assays; electron microscopy of replication forks; siRNA knockdown; inhibitor studies; epistasis analysis in BRCA2-deficient cells Nature communications High 29038425
2009 In cells lacking MRN, ATM is not activated when TRF2 is removed from telomeres and LIG4-dependent chromosome end fusions are markedly reduced; MRE11 nuclease activity removes the 3' telomeric overhang to promote NHEJ-mediated chromosome fusions after TRF2 loss; MRE11 also promotes 5'-strand resection at leading-strand telomeres to generate POT1a-TPP1-bound 3' overhangs. Conditional MRE11 complex knockout mouse alleles; MRE11 nuclease-dead alleles; TRF2 cre-mediated inactivation; cytogenetic analysis of chromosome fusions; telomere FISH Nature High 19633651
2014 LSD1 is recruited to uncapped telomeres via TERRA and associates with MRE11; LSD1 is required for efficient removal of 3' telomeric G-overhangs; LSD1 enhances MRE11 nuclease activity in vitro and in vivo; TERRA upregulation reinforces the LSD1-MRE11 interaction. Co-immunoprecipitation; in vitro nuclease stimulation assay; RNA immunoprecipitation; TRF2-depleted cell system Cell reports High 24529708
2007 Rad50 adenylate kinase activity promotes DNA tethering by Mre11/Rad50 complexes; mutation of the conserved Rad50 signature motif reduces adenylate kinase activity without affecting ATPase; adenylate kinase inhibitor blocks Mre11/Rad50-dependent DNA tethering in vitro and in cell-free extracts; the adenylate kinase mutant phenocopies rad50 null in meiosis and telomere maintenance. In vitro adenylate kinase assay; DNA tethering assay in Xenopus extracts; S. cerevisiae genetic analysis; signature motif mutagenesis Molecular cell High 17349953
2015 ATP-dependent conformational changes in the Mre11/Rad50 complex regulate DNA melting and endonuclease activity; the crystal structure of Methanococcus jannaschii MR with ATPγS and DNA shows DNA running symmetrically across the central groove between two Rad50 nucleotide-binding domains; ATP hydrolysis drives rotation of Rad50 nucleotide-binding domains, inducing DNA melting to allow substrate access to Mre11 active site. Crystal structure of archaeal Mre11/Rad50-ATPγS-DNA complex; biochemical unwinding and nuclease assays The EMBO journal High 26717941
2004 Mre11 complex functions together with Exo1 to generate long ssDNA tails at DSBs, promoting Mec1 (ATR ortholog) association with DSBs and activation of the Mec1 checkpoint signaling pathway after DNA damage and replication block. Genetic epistasis in S. cerevisiae; DSB resection assays; Mec1 chromatin immunoprecipitation at DSBs Molecular and cellular biology High 15509802
2016 Cyclin A2 binds Mre11 mRNA through a C-terminal RNA binding domain to mediate polysome loading and translation of Mre11 in S phase; this kinase-independent function is required for adequate Mre11 levels to resolve stalled replication forks and repair DSBs. mRNA immunoprecipitation; polysome fractionation; cyclin A2 RNA binding domain identification; conditional mouse mutants; DNA fiber assays Science High 27708105
2022 Mre11-Rad50 forms higher-order oligomeric assemblies on DNA mediated by a conserved Rad50 beta-sheet; oligomerization drives endonucleolytic cleavage at multiple sites on the 5'-DNA strand near DSBs but does not affect exonuclease activity; oligomerization facilitates DSB foci formation, DNA damage signaling, repair, and telomere maintenance in vivo. Electron microscopy; biochemical oligomerization assays; Rad50 beta-sheet mutations; in vivo genetic studies in S. cerevisiae; reconstituted pathway analysis Nature communications High 35501303
2024 MRE11 (within the MRN complex) binds nucleosome fragments to displace cGAS from acidic-patch-mediated sequestration, enabling cGAS mobilization and activation by dsDNA; MRE11 is essential for cGAS activation in response to oncogenic stress, cytosolic dsDNA, and ionizing radiation; MRE11-dependent cGAS activation promotes ZBP1-RIPK3-MLKL-mediated necroptosis to suppress tumorigenesis. Biochemical binding assays (MRN-nucleosome vs. cGAS); cGAS activity assays; genetic loss-of-function (MRE11 depletion); necroptosis pathway analysis; mouse mammary tumor models Nature High 38200309
2022 RNF126 E3 ubiquitin ligase ubiquitinates MRE11 at K339 and K480, increasing its DNA exonuclease activity, subsequent RPA binding, and ATR phosphorylation to promote sustained DDR via HR. Co-immunoprecipitation; in vitro ubiquitination assay; exonuclease activity assay; RPA binding assay; ATR-CHK1 signaling analysis; RNF126 knockdown/overexpression Advanced science High 36563124
2022 METTL16 interacts with MRE11 through RNA and inhibits MRE11's exonuclease activity in a methyltransferase-independent manner, repressing DNA end resection; upon DNA damage, ATM phosphorylates METTL16 causing a conformational change and autoinhibition of its RNA binding, dissociating the METTL16-RNA-MRE11 complex and releasing inhibition of MRE11. Co-immunoprecipitation; in vitro exonuclease assays; ATM phosphorylation of METTL16; conformational change analysis; resection assays Nature cancer High 36138131
2022 MRE11 requires SUMOylation (promoted by PIAS1 on chromatin at DSBs) to shield it from ubiquitin-mediated proteasomal degradation during resection; after MRE11 moves away from DSB sites, SENP3 deSUMOylates it; SENP3 deficiency causes MRE11 accumulation on chromatin and genome instability. Co-immunoprecipitation; in vivo SUMOylation assays; SENP3 and PIAS1 knockdown; chromatin fractionation; DSB resection assays; cancer mutant analysis Nature communications High 36050397
2018 GFI1 interacts with PRMT1 and its substrates MRE11 and 53BP1, enabling PRMT1 to bind and methylate MRE11; GFI1 is required for efficient PRMT1-mediated MRE11 arginine methylation, which is necessary for MRE11 function in the DNA damage response. Co-immunoprecipitation; in vitro methylation assays; GFI1 knockout T cells; immunofluorescence of DSB foci Nature communications High 29651020
2011 MRE11 is the major nuclease responsible for increased DNA end-degradation and microhomology-mediated end joining (MMEJ) repair in ATM-deficient cells; ATM kinase activity suppresses Mre11-dependent DNA end-degradation; Mre11 knockdown and nuclease inhibitor (mirin) decrease MMEJ in mammalian cells. In vivo MMEJ reporter assay; Mre11 knockdown; mirin inhibitor; ATM kinase assays; structural modeling of Mre11 dimer engaging DNA ends Cell cycle High 20647759
2011 MRE11 promotes AKT phosphorylation at S473 in response to DSBs via a signaling cascade dependent on MRE11-ATM-RNF168; this is independent of MRE11 endonuclease domain, DNA-PKcs, PI3K, and ATR; pAKT-S473 co-localizes with γH2AX and ATM-pS1981 at DSBs. Whole-cell IR; nuclear UV microbeam; endonuclease-induced DSBs; MRE11 siRNA; inhibitor studies (DNA-PKcs, PI3K, ATR); immunofluorescence co-localization Cell cycle Medium 21623170
2004 WRN (Werner syndrome helicase) associates with the Mre11 complex via direct binding to Nbs1 in vitro and in vivo; in response to γ-irradiation or mitomycin C, WRN co-localizes with the Mre11 complex in the nucleoplasm; Nbs1 is required for the Mre11 complex-mediated promotion of WRN helicase activity. Co-immunoprecipitation in vitro and in vivo; immunofluorescence co-localization; WRN helicase activity assay; siRNA and complementation experiments The Journal of biological chemistry High 15026416
2016 Nuclear localization of Mre11 (Mre11-NLS) bypasses Xrs2 requirement for DNA end resection, meiosis, hairpin resolution, and cellular resistance to clastogens; purified MR complex has equivalent endonuclease activity to MRX on protein-blocked DNA ends; Xrs2 serves as a chaperone/adaptor for nuclear translocation and for Tel1/ATM signaling and NHEJ but not for MR nuclease activities. Mre11-NLS rescue experiments in xrs2Δ yeast; in vitro nuclease assays with purified MR vs. MRX; epistasis with Sae2; ChIP and genetic assays Molecular cell High 27746018
2017 The Mre11-Nbs1 interaction interface is essential for viability; a 108-amino-acid Nbs1 fragment comprising the Mre11-binding domain rescues viability, ATM activation, and hematopoietic differentiation; this indicates the essential role of Nbs1 is via its interaction with Mre11 and that Mre11 and Rad50 can directly activate ATM. TALEN-based Nbs1 interaction domain mutations in mice; conditional knockin; hematopoietic cell differentiation assays; ATM activation assays in cultured cells Cell reports High 28076792
2002 Human Rad50/Mre11 (R/M) complex binds both single-stranded and double-stranded DNA; forms oligomeric complexes at DNA ends that can migrate away; ATP binding (not hydrolysis) increases R/M preference for 3'-overhang substrates over blunt or 5'-overhang substrates. Scanning force microscopy; DNA binding assays with ATP, ATPγS, and ADP; defined DNA substrate comparison Nucleic acids research High 12384589
2021 PARP14 mono-ADP-ribosylates MRE11, facilitating its engagement at stalled replication forks in BRCA-deficient cells; KU complex binds reversed forks protecting them against EXO1 degradation and recruits PARP14-MRE11 complex; MRE11 initiates partial resection to release KU, enabling long-range EXO1 resection. iPOND; DNA fiber assays; PARP14 inhibitor and knockdown; epistasis with KU, MRE11, and EXO1; chromatin fractionation Nature communications High 36030235
2020 p97/VCP physically and functionally interacts with the MRN complex on chromatin; p97 inactivation blocks MRN complex disassembly from DSB sites, resulting in excessive MRE11-mediated 5'-DNA end resection and defective DSB repair. Co-immunoprecipitation; chromatin fractionation; resection assays; p97 inhibitor CB-5083; in vitro and in vivo radiosensitivity assays Cell reports High 34038735
2021 GRB2 forms a validated GRB2-MRE11 (GM) complex; GRB2-SH2 domain targets the GM complex to phosphorylated H2AX (γH2AX) at DSBs; GRB2 K109 ubiquitination by E3 ligase RBBP6 releases MRE11 to promote HDR; GRB2 knockout increases MRE11-XRCC1 complex and alternative end joining instead. Biophysical binding validation of GRB2-MRE11 complex; co-immunoprecipitation; ubiquitination assay; HDR and Alt-EJ repair assays; GRB2 separation-of-function mutants Science advances High 34348893
2022 POLθ processes stalled Okazaki fragments, suppressing lagging-strand ssDNA gaps in RAD51-deficient cells; in the absence of POLθ, ssDNA gaps enable MRE11-NBS1-CtIP endonuclease to cleave replication forks producing asymmetric single-ended DSBs. Xenopus laevis cell-free system; electron microscopy direct visualization of Okazaki fragments; MRE11 inhibition; BRCA2-deficient cell survival assays Molecular cell High 36400008
2021 Loss of ATM or Mre11 ATLD mutants (but not Nbs1) leads to PARP-dependent formation of insoluble protein aggregates arising from intrinsically disordered proteins associating with PAR-associated genomic sites; the lesions are ssDNA breaks dependent on reactive oxygen species, transcription, and R-loops; this mechanism is proposed to account for protein integrity loss in A-T cerebellum. Human cell PARP inhibition; insoluble protein fractionation; A-T patient cerebellum samples; proteomics Molecular cell Medium 33571423
2021 MRE11 nuclease degrades nascent mitochondrial DNA (mtDNA) at stalled replication forks in Fanconi anemia patient cells; chemical inhibition of MRE11 suppresses hyperactivation of cGAS-STING innate immune signaling triggered by degraded mtDNA. DNA fiber assay for mtDNA; MRE11 inhibitor (mirin); cGAS-STING signaling assays; Fanconi anemia patient cells Science advances Medium 34910513
2016 MRE11A nuclease deficiency in human CD4+ T cells leads to telomeric damage, juxtacentromeric heterochromatin unraveling, and senescence marker upregulation; inhibition of MRE11A activity in healthy T cells induces the aging phenotype, while MRE11A overexpression in RA T cells reverses it. MRE11A expression manipulation (knockdown and overexpression); telomere integrity assays; senescence marker analysis; human-synovium chimeric mouse model Immunity Medium 27742546
2020 CDC7 kinase localizes at replication forks and phosphorylates MRE11; CDC7 activity is required to coordinate MRE11-dependent fork slowing upon topoisomerase inhibition, retaining MRE11 on stalled forks for processing and restart; CDC7 also mediates pathological MRE11-dependent degradation of reversed forks in BRCA2-deficient cells. Chemical genetic CDC7 inhibition; DNA fiber assays; MRE11 phosphorylation analysis; iPOND; electron microscopy of fork structures; BRCA2-deficient cell analysis EMBO reports Medium 32496651
2023 Replication stress-induced ssDNA gaps are extended bidirectionally by MRE11 (3'→5') and EXO1 (5'→3'); subsequently, MRE11 endonuclease cleaves the parental strand at the ssDNA gap to generate DSBs; this process is suppressed by the BRCA pathway. DNA fiber assays; ssDNA gap quantification; MRE11 and EXO1 inhibition/knockdown; BRCA pathway epistasis; BPA/DEHP exposure model Nature communications High 37805499

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 The Mre11 complex: at the crossroads of dna repair and checkpoint signalling. Nature reviews. Molecular cell biology 695 11988766
2004 Direct activation of the ATM protein kinase by the Mre11/Rad50/Nbs1 complex. Science (New York, N.Y.) 600 15064416
2000 Cell-cycle-regulated association of RAD50/MRE11/NBS1 with TRF2 and human telomeres. Nature genetics 491 10888888
2013 DNA double-strand break repair pathway choice is directed by distinct MRE11 nuclease activities. Molecular cell 467 24316220
1999 Nbs1 potentiates ATP-driven DNA unwinding and endonuclease cleavage by the Mre11/Rad50 complex. Genes & development 434 10346816
2008 Mre11 dimers coordinate DNA end bridging and nuclease processing in double-strand-break repair. Cell 405 18854158
2011 Bidirectional resection of DNA double-strand breaks by Mre11 and Exo1. Nature 364 22002605
2023 Metabolic regulation of homologous recombination repair by MRE11 lactylation. Cell 354 38128537
2017 MRE11 and EXO1 nucleases degrade reversed forks and elicit MUS81-dependent fork rescue in BRCA2-deficient cells. Nature communications 339 29038425
2001 Promotion of Dnl4-catalyzed DNA end-joining by the Rad50/Mre11/Xrs2 and Hdf1/Hdf2 complexes. Molecular cell 243 11741545
2001 Mre11 protein complex prevents double-strand break accumulation during chromosomal DNA replication. Molecular cell 207 11511367
2019 MRE11-RAD50-NBS1 complex alterations and DNA damage response: implications for cancer treatment. Molecular cancer 199 31767017
2004 Ataxia-telangiectasia-like disorder (ATLD)-its clinical presentation and molecular basis. DNA repair 194 15279810
2010 Mre11-Rad50-Xrs2 and Sae2 promote 5' strand resection of DNA double-strand breaks. Nature structural & molecular biology 190 21102445
2018 DYNLL1 binds to MRE11 to limit DNA end resection in BRCA1-deficient cells. Nature 188 30464262
2006 Two-step activation of ATM by DNA and the Mre11-Rad50-Nbs1 complex. Nature structural & molecular biology 186 16622404
2000 The Mre11 complex and ATM: collaborating to navigate S phase. Current opinion in cell biology 181 10801460
2009 Multiple roles for MRE11 at uncapped telomeres. Nature 158 19633651
2017 Single-Molecule Imaging Reveals How Mre11-Rad50-Nbs1 Initiates DNA Break Repair. Molecular cell 151 28867292
2016 Nbs1 Converts the Human Mre11/Rad50 Nuclease Complex into an Endo/Exonuclease Machine Specific for Protein-DNA Adducts. Molecular cell 141 27814491
2019 MRE11 UFMylation promotes ATM activation. Nucleic acids research 134 30783677
2018 20 Years of Mre11 Biology: No End in Sight. Molecular cell 122 30057197
1995 Isolation and characterization of the human MRE11 homologue. Genomics 114 8530104
2002 Tethering on the brink: the evolutionarily conserved Mre11-Rad50 complex. Trends in biochemical sciences 113 12151226
2004 MRE11/RAD50/NBS1: complex activities. Chromosoma 109 15309560
2016 Deficient Activity of the Nuclease MRE11A Induces T Cell Aging and Promotes Arthritogenic Effector Functions in Patients with Rheumatoid Arthritis. Immunity 108 27742546
2014 TERRA-reinforced association of LSD1 with MRE11 promotes processing of uncapped telomeres. Cell reports 107 24529708
2019 Mechanism of DNA End Sensing and Processing by the Mre11-Rad50 Complex. Molecular cell 106 31492634
2024 MRE11 liberates cGAS from nucleosome sequestration during tumorigenesis. Nature 105 38200309
2011 MRE11 promotes AKT phosphorylation in direct response to DNA double-strand breaks. Cell cycle (Georgetown, Tex.) 100 21623170
2015 ATP-dependent DNA binding, unwinding, and resection by the Mre11/Rad50 complex. The EMBO journal 99 26717941
2007 The multiple roles of the Mre11 complex for meiotic recombination. Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology 99 17674145
2004 Linkage between Werner syndrome protein and the Mre11 complex via Nbs1. The Journal of biological chemistry 98 15026416
2004 Requirement of the Mre11 complex and exonuclease 1 for activation of the Mec1 signaling pathway. Molecular and cellular biology 91 15509802
2011 The MRE11 GAR motif regulates DNA double-strand break processing and ATR activation. Cell research 88 21826105
2007 Rad50 adenylate kinase activity regulates DNA tethering by Mre11/Rad50 complexes. Molecular cell 87 17349953
2004 Mre11 assembles linear DNA fragments into DNA damage signaling complexes. PLoS biology 87 15138496
2009 MRE11-RAD50-NBS1 complex dictates DNA repair independent of H2AX. The Journal of biological chemistry 84 19910469
2020 The MRE11 complex: A versatile toolkit for the repair of broken DNA. DNA repair 82 32480356
2014 Rare key functional domain missense substitutions in MRE11A, RAD50, and NBN contribute to breast cancer susceptibility: results from a Breast Cancer Family Registry case-control mutation-screening study. Breast cancer research : BCR 80 24894818
2009 Differential DNA damage signaling accounts for distinct neural apoptotic responses in ATLD and NBS. Genes & development 80 19171781
2002 DNA cross-link-dependent RAD50/MRE11/NBS1 subnuclear assembly requires the Fanconi anemia C protein. Human molecular genetics 80 12354779
2008 A glycine-arginine domain in control of the human MRE11 DNA repair protein. Molecular and cellular biology 77 18285453
2014 Effect of MRE11 loss on PARP-inhibitor sensitivity in endometrial cancer in vitro. PloS one 74 24927325
2018 Role of the Mre11 Complex in Preserving Genome Integrity. Genes 70 30501098
2011 Brca2, Rad51 and Mre11: performing balancing acts on replication forks. DNA repair 69 21900052
2022 POLθ prevents MRE11-NBS1-CtIP-dependent fork breakage in the absence of BRCA2/RAD51 by filling lagging-strand gaps. Molecular cell 68 36400008
2007 The Mre11 complex influences DNA repair, synapsis, and crossing over in murine meiosis. Current biology : CB 67 17291760
2016 Xrs2 Dependent and Independent Functions of the Mre11-Rad50 Complex. Molecular cell 66 27746018
2010 ATM regulates Mre11-dependent DNA end-degradation and microhomology-mediated end joining. Cell cycle (Georgetown, Tex.) 66 20647759
2016 Cyclin A2 is an RNA binding protein that controls Mre11 mRNA translation. Science (New York, N.Y.) 63 27708105
2004 Independent roles for nibrin and Mre11-Rad50 in the activation and function of Atm. The Journal of biological chemistry 63 15234984
1995 Functions of the yeast meiotic recombination genes, MRE11 and MRE2. Advances in biophysics 58 7625279
2022 RNF126-Mediated MRE11 Ubiquitination Activates the DNA Damage Response and Confers Resistance of Triple-Negative Breast Cancer to Radiotherapy. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 57 36563124
2022 METTL16 antagonizes MRE11-mediated DNA end resection and confers synthetic lethality to PARP inhibition in pancreatic ductal adenocarcinoma. Nature cancer 56 36138131
2013 Visualization of local DNA unwinding by Mre11/Rad50/Nbs1 using single-molecule FRET. Proceedings of the National Academy of Sciences of the United States of America 56 24191051
2009 The mre11 complex and the response to dysfunctional telomeres. Molecular and cellular biology 54 19667076
2017 Plk1 Phosphorylation of Mre11 Antagonizes the DNA Damage Response. Cancer research 53 28512243
2018 GFI1 facilitates efficient DNA repair by regulating PRMT1 dependent methylation of MRE11 and 53BP1. Nature communications 52 29651020
2015 Mre11-Sae2 and RPA Collaborate to Prevent Palindromic Gene Amplification. Molecular cell 52 26545079
2008 Dancing on damaged chromatin: functions of ATM and the RAD50/MRE11/NBS1 complex in cellular responses to DNA damage. Journal of radiation research 51 18772547
2005 The MRE11-RAD50-NBS1 complex accelerates somatic hypermutation and gene conversion of immunoglobulin variable regions. Nature immunology 51 15937485
2002 DNA end-binding specificity of human Rad50/Mre11 is influenced by ATP. Nucleic acids research 51 12384589
2021 UFMylation of MRE11 is essential for telomere length maintenance and hematopoietic stem cell survival. Science advances 50 34559557
2010 Biochemical characterization of bacteriophage T4 Mre11-Rad50 complex. The Journal of biological chemistry 50 21081488
2022 Cryo-EM structure of the Mre11-Rad50-Nbs1 complex reveals the molecular mechanism of scaffolding functions. Molecular cell 49 36577401
2011 Two unrelated patients with MRE11A mutations and Nijmegen breakage syndrome-like severe microcephaly. DNA repair 49 21227757
2004 Structural and functional analysis of Mre11-3. Nucleic acids research 48 15047855
2002 SV40 large T-antigen disturbs the formation of nuclear DNA-repair foci containing MRE11. Oncogene 47 12118365
2008 Functional interactions between Sae2 and the Mre11 complex. Genetics 46 18245357
2017 AKT overactivation can suppress DNA repair via p70S6 kinase-dependent downregulation of MRE11. Oncogene 44 28967905
2021 Poly-ADP-ribosylation drives loss of protein homeostasis in ATM and Mre11 deficiency. Molecular cell 43 33571423
2017 The Mre11-Nbs1 Interface Is Essential for Viability and Tumor Suppression. Cell reports 41 28076792
2013 Disease-associated MRE11 mutants impact ATM/ATR DNA damage signaling by distinct mechanisms. Human molecular genetics 41 23912341
2010 Mre11 nuclease activity and Ctp1 regulate Chk1 activation by Rad3ATR and Tel1ATM checkpoint kinases at double-strand breaks. Molecular and cellular biology 41 21098122
2014 The Mre11/Rad50/Nbs1 complex: recent insights into catalytic activities and ATP-driven conformational changes. Experimental cell research 40 25016281
2002 The plant Rad50-Mre11 protein complex. FEBS letters 39 11959125
2022 The KU-PARP14 axis differentially regulates DNA resection at stalled replication forks by MRE11 and EXO1. Nature communications 38 36030235
2021 MRE11-dependent instability in mitochondrial DNA fork protection activates a cGAS immune signaling pathway. Science advances 37 34910513
2014 Next-generation sequencing identifies germline MRE11A variants as markers of radiotherapy outcomes in muscle-invasive bladder cancer. Annals of oncology : official journal of the European Society for Medical Oncology 37 24623370
2022 Mre11-Rad50 oligomerization promotes DNA double-strand break repair. Nature communications 35 35501303
2019 Perturbing cohesin dynamics drives MRE11 nuclease-dependent replication fork slowing. Nucleic acids research 35 29917110
2019 The ATP-bound conformation of the Mre11-Rad50 complex is essential for Tel1/ATM activation. Nucleic acids research 35 30698745
2011 MRE11 and RAD50, but not NBS1, are essential for gene targeting in the moss Physcomitrella patens. Nucleic acids research 35 22210882
2022 Crosstalk between SUMOylation and ubiquitylation controls DNA end resection by maintaining MRE11 homeostasis on chromatin. Nature communications 34 36050397
2006 Purification and biochemical characterization of ataxia-telangiectasia mutated and Mre11/Rad50/Nbs1. Methods in enzymology 34 16793391
2023 Multi-step processing of replication stress-derived nascent strand DNA gaps by MRE11 and EXO1 nucleases. Nature communications 33 37805499
2022 Structural mechanism of endonucleolytic processing of blocked DNA ends and hairpins by Mre11-Rad50. Molecular cell 33 35987200
2011 ATP hydrolysis by RAD50 protein switches MRE11 enzyme from endonuclease to exonuclease. The Journal of biological chemistry 33 22102415
2021 GRB2 enforces homology-directed repair initiation by MRE11. Science advances 32 34348893
2021 p97/VCP inhibition causes excessive MRE11-dependent DNA end resection promoting cell killing after ionizing radiation. Cell reports 31 34038735
2020 A Survey of Reported Disease-Related Mutations in the MRE11-RAD50-NBS1 Complex. Cells 30 32668560
2012 Ataxia-telangiectasia mutated and the Mre11-Rad50-NBS1 complex: promising targets for radiosensitization. Acta medica Okayama 30 22525466
2021 MRE11 as a molecular signature and therapeutic target for cancer treatment with radiotherapy. Cancer letters 29 34022282
2020 CDC7 kinase promotes MRE11 fork processing, modulating fork speed and chromosomal breakage. EMBO reports 27 32496651
2013 Sequencing of candidate chromosome instability genes in endometrial cancers reveals somatic mutations in ESCO1, CHTF18, and MRE11A. PloS one 27 23755103
2019 Elevated MRE11 expression associated with progression and poor outcome in prostate cancer. Journal of Cancer 26 31413753
2023 Dynamics of the DYNLL1-MRE11 complex regulate DNA end resection and recruitment of Shieldin to DSBs. Nature structural & molecular biology 25 37696958
2006 Rad50S alleles of the Mre11 complex: questions answered and questions raised. Experimental cell research 24 16857186
2023 Mre11-Rad50: the DNA end game. Biochemical Society transactions 23 36892213