Affinage

NEIL3

Endonuclease 8-like 3 · UniProt Q8TAT5

Length
605 aa
Mass
67.8 kDa
Annotated
2026-06-10
67 papers in source corpus 31 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 10/10 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NEIL3 is a DNA glycosylase of the Fpg/Nei superfamily that initiates base excision repair of oxidized DNA lesions, with a marked preference for single-stranded DNA and replication-fork structures (PMID:20185759, PMID:31018584). It excises oxidized purine hydantoins (spiroiminodihydantoin, guanidinohydantoin), FapyG, FapyA, and thymine glycol, but not 8-oxoG (PMID:20185759, PMID:23755964), and uniquely among mammalian glycosylases removes thymine glycol from quadruplex/telomeric DNA (PMID:23926102). Unlike its paralogs NEIL1/NEIL2, NEIL3 acts as a monofunctional glycosylase (β-elimination only) using its N-terminal valine rather than proline as the catalytic nucleophile to form a Schiff base intermediate; the V2P mutation converts it to a bifunctional enzyme and Lys81 is essential for catalysis (PMID:20185759, PMID:23755964). Structural studies of the mouse glycosylase domain explain both its inability to excise 8-oxoG (loss of the αF-β9/10 capping loop) and its ssDNA preference (an unfavorable electrostatic environment for the opposite strand) (PMID:23313161). Its C-terminal tandem GRF zinc-finger domain binds ssDNA and replication-fork structures with high affinity, autoinhibits glycosylase activity, and mediates an interaction with APE1 that suppresses aberrant APE1 endonuclease cleavage of ssDNA (PMID:32878989, PMID:36155818, PMID:32817342). NEIL3 defines a replication-coupled, incision-independent pathway for unhooking interstrand cross-links: it cleaves one of the two N-glycosyl bonds of psoralen- and abasic-site-derived ICLs without generating double-strand breaks, acting upstream of and as the preferred route over the FANCI-FANCD2/Fanconi anemia pathway, which is engaged only when N-glycosyl cleavage fails (PMID:27693351, PMID:31923807, PMID:29234069). During S/G2 phase NEIL3 is recruited to telomeres through interaction with TRF1 and to ICLs through PARP- and TRAIP-dependent signaling, cooperating with RUVBL1/2, PCNA, and FEN1 to repair oxidative and cross-link damage and prevent telomere dysfunction and anaphase bridging (PMID:28854357, PMID:31980815, PMID:34045188). Through its GRF domain NEIL3 also promotes the homologous-recombination step of FA/BRCA ICL repair by recruiting the resection machinery CtIP, MRN, and DNA2 (PMID:36351389, PMID:29348879). Beyond DNA repair, NEIL3 interacts with the EMT factor TWIST1 to drive proliferation and drug-resistance gene programs in cancer, and its expression is cell-cycle regulated via the Ras-ERK pathway and transcriptionally controlled by E2F1 (PMID:22365498, PMID:36181299, PMID:37992567). Knockout mouse studies link NEIL3 to neural stem/progenitor self-renewal, hippocampal neurogenesis, and cardiac fibroblast regulation (PMID:23305905, PMID:22065741, PMID:28052262).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2010 High

    Establishing NEIL3 as a bona fide glycosylase answered whether this Fpg/Nei member had catalytic activity and defined its unusual substrate range and chemistry.

    Evidence In vitro glycosylase assays, Schiff-base trapping, and E. coli triple-mutant complementation with mouse Neil3

    PMID:20185759

    Open questions at the time
    • Did not resolve the structural basis for ssDNA preference
    • Human enzyme catalytic mode not yet defined
  2. 2013 High

    Defining the catalytic mechanism and structure clarified why NEIL3 is monofunctional and ssDNA-selective and cannot process 8-oxoG.

    Evidence Active-site mutagenesis (V2P, K81) and a 2.0 Å crystal structure of the mouse glycosylase domain with substrate profiling including quadruplex DNA

    PMID:23313161 PMID:23755964 PMID:23926102

    Open questions at the time
    • Did not address how the C-terminal GRF domain regulates catalysis
    • In-cell substrate spectrum not established
  3. 2008 Medium

    An early biochemical characterization established AP lyase activity specific for ssDNA and the requirement of the N-terminus and zinc-finger motif.

    Evidence In vitro AP lyase assays with deletion/zinc-finger mutants and E. coli complementation of human NEIL3

    PMID:19170771

    Open questions at the time
    • No glycosylase activity on modified bases detected in this study
    • Single lab, no replication
  4. 2016 High

    Discovery of incision-independent ICL unhooking answered how cross-links can be repaired without double-strand breaks and placed NEIL3 upstream of the Fanconi anemia pathway.

    Evidence Xenopus egg-extract replication-coupled repair with genetic epistasis against FANCI-FANCD2 and biochemical unhooking assays

    PMID:27693351

    Open questions at the time
    • Recruitment signal to the fork not yet defined
    • Structural basis of ICL recognition unresolved
  5. 2017 High

    Identifying telomeric recruitment and BER partner interactions established a cell-cycle-coupled role at telomeres and connected NEIL3 to long-patch BER.

    Evidence Co-IP and co-localization with TRF1/TRF2, in vitro activity enhancement by TRF1, anaphase-bridge quantification in knockdown cells; psoralen-ICL cleavage in multi-stranded substrates

    PMID:28854357 PMID:29234069

    Open questions at the time
    • How TRF1 enhances enzymatic activity mechanistically unknown
    • Telomere vs. genome-wide division of labor not quantified
  6. 2019 High

    Defining replication-fork geometry preference showed that NEIL3 acts on lesions on the leading template strand and shares fork substrates with NEIL1.

    Evidence In vitro unhooking and glycosylase assays on splayed-duplex and model fork substrates with site-specific dA-AP ICLs, DHT, and oxidized bases

    PMID:31018584 PMID:31923807

    Open questions at the time
    • Single-lab fork substrate models
    • Coordination with NEIL1 in cells not demonstrated
  7. 2020 High

    Characterizing the GRF domain and its partners answered how NEIL3 binds ssDNA, restrains its own activity, and controls APE1 during repair.

    Evidence Crystal structure of the tandem GRF domain, ssDNA-binding and autoinhibition assays, APE1/RUVBL1-2 pull-downs and activity assays, PARP/TRAIP epistasis in human cells

    PMID:31980815 PMID:32817342 PMID:32878989

    Open questions at the time
    • How autoinhibition is relieved at the lesion is unclear
    • TRAIP-to-NEIL3 recruitment signal not biochemically defined
  8. 2022 High

    Structural modeling of GRF-DNA and catalytic-domain-intermediate complexes provided a coherent model for how the two domains cooperate to recognize an ICL at a replication X-structure.

    Evidence Two crystal structures (GRF-DNA; NEI domain-DNA intermediate) with biochemical ssDNA-binding validation

    PMID:36155818

    Open questions at the time
    • Full-length enzyme-fork complex not solved
    • Dynamics of domain handoff not captured
  9. 2022 Medium

    Defining a GRF-dependent role in HR resection answered how NEIL3 also contributes to the Fanconi-anemia/BRCA branch of ICL repair when used for MMC and cisplatin lesions.

    Evidence Co-IP with CtIP/MRN/DNA2, chromatin fractionation, end-resection and HR reporter assays with knockdowns; complemented by iPOND-based fork data

    PMID:29348879 PMID:36351389

    Open questions at the time
    • Whether resection role requires glycosylase activity is unresolved
    • Direct vs. bridging interactions with resection factors not distinguished
  10. 2021 Medium

    Telomere-specific oxidative repair during mitosis established NEIL3 as the dedicated initiator of APE1/POLB BER at oxidized telomeres, distinct from NEIL1/NEIL2.

    Evidence META-FISH, co-localization with TRF2 and APE1, telomere-damage quantification with paralog comparison in HCC cells

    PMID:34045188

    Open questions at the time
    • Single cancer-cell context
    • Mechanism of mitosis-specific recruitment not defined
  11. 2023 Medium

    Identifying proteasome-dependent WRNIP1 degradation suggested NEIL3 also coordinates the lesion-recognition-to-repair transition at ICL-stalled forks.

    Evidence Proteomics, Co-IP of NEIL3 with 26S proteasome, and WRNIP1 degradation assays under cisplatin

    PMID:36997601

    Open questions at the time
    • Whether NEIL3 directly targets WRNIP1 to the proteasome unclear
    • Single lab, single study
  12. 2022 Medium

    Linking NEIL3 to TWIST1 and to E2F1 transcriptional circuits revealed non-canonical, repair-independent roles in cancer proliferation and drug resistance.

    Evidence Co-IP of NEIL3-TWIST1, promoter reporters, RNA-seq and orthotopic models in HCC; ChIP/reporter for E2F1-NEIL3 feedback in renal carcinoma

    PMID:28052262 PMID:36181299

    Open questions at the time
    • Whether the glycosylase activity is required for transcriptional functions unknown
    • Direct vs. indirect TWIST1 cooperation not fully resolved
  13. 2012 Medium

    Cell-cycle and pathway regulation of NEIL3 expression connected it to replication-associated repair, paralleling FEN1.

    Evidence Cell-cycle synchronization, ERK-pathway inhibition, and qRT-PCR/Western analysis of human NEIL3

    PMID:22365498

    Open questions at the time
    • Direct transcription factors at the promoter not all identified here
    • Link to repair function correlative
  14. 2012 Medium

    Knockout mouse phenotyping established physiological roles of NEIL3 in neural stem-cell self-renewal, neurogenesis, and behavior, and confirmed it as the principal ssDNA hydantoin glycosylase in tissue.

    Evidence Neil3-/- mice with neurosphere, MEF proliferation, behavioral, electron-microscopy, hypoxia-ischemia, and tissue-extract glycosylase assays

    PMID:22065741 PMID:22959434 PMID:23305905

    Open questions at the time
    • Whether neural phenotypes require glycosylase activity not established
    • Causal repair-to-phenotype link inferred
  15. 2025 Low

    Recent knockout studies attributed neural and behavioral phenotypes to transcriptional/epigenetic rather than genomic-integrity mechanisms, including Wnt-pathway and DNA-methylation effects.

    Evidence Neil3-/- mice with electrophysiology, fear conditioning, neurosphere assays, RNA-seq, bisulfite sequencing, and Wnt-inhibitor experiments

    PMID:40035863 PMID:41015225

    Open questions at the time
    • Direct biochemical link between NEIL3 and Wnt/methylation not established
    • Single-lab models without independent replication
  16. 2022 Medium

    Cardiovascular knockout studies indicated non-canonical roles for NEIL3 in cardiac fibroblast and vascular smooth muscle cell behavior, possibly via epigenetic and Akt signaling.

    Evidence Neil3-/- mouse MI and Apoe-/- models, human VSMC knockdown, 5mC/5hmC profiling, Akt phosphorylation and inhibitor assays, scRNA-seq

    PMID:28052262 PMID:33714552

    Open questions at the time
    • Mechanism connecting NEIL3 to DNA methylation and Akt is correlative
    • Effects reported without changes in DNA damage levels

Open questions

Synthesis pass · forward-looking unresolved questions
  • How NEIL3's canonical glycosylase chemistry relates mechanistically to its repair-independent transcriptional, epigenetic, and signaling roles remains unresolved.
  • No experiment separates catalytic-dependent from catalytic-independent functions in vivo
  • No structure of the full-length enzyme engaging a replication fork
  • No direct demonstration that NEIL3 enzymatically alters DNA methylation marks

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140097 catalytic activity, acting on DNA 8 GO:0003677 DNA binding 4 GO:0016787 hydrolase activity 4 GO:0140110 transcription regulator activity 1
Localization
GO:0000228 nuclear chromosome 3 GO:0005634 nucleus 1
Pathway
R-HSA-69306 DNA Replication 4 R-HSA-73894 DNA Repair 4 R-HSA-1640170 Cell Cycle 2
Partners
APE1CTIPDNA2FEN1PCNARUVBL1TRF1TWIST1

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 NEIL3 acts as a DNA glycosylase that unhooks interstrand cross-links (ICLs) derived from psoralen and abasic sites by cleaving one of the two N-glycosyl bonds forming the cross-link, providing a replication-coupled, incision-independent ICL repair pathway that avoids double-strand break formation. When N-glycosyl bond cleavage is blocked, repair reverts to FANCI-FANCD2-dependent incisions. Xenopus egg extract cell-free replication system; genetic epistasis (NEIL3 depletion vs. FANCI-FANCD2 depletion); biochemical ICL unhooking assays Cell High 27693351
2010 Mouse Neil3 (MmuNeil3) is a functional DNA glycosylase that excises oxidized purines Sp, Gh, FapyG, and FapyA from duplex DNA, but not 8-oxoG. It preferentially acts on single-stranded DNA and bubble structures. Unlike other Fpg/Nei family members that use an N-terminal proline as nucleophile, MmuNeil3 forms a Schiff base intermediate via its N-terminal valine. In vivo, expression in an E. coli triple glycosylase mutant reduced spontaneous mutation frequency and FapyG levels. In vitro glycosylase assays on defined substrates; Schiff base trapping; in vivo complementation of E. coli fpg nei mutY triple mutant; GC-MS measurement of FapyG Proceedings of the National Academy of Sciences of the United States of America High 20185759
2013 Human NEIL3 glycosylase domain (GD) efficiently excises hydantoin lesions Sp and Gh from ssDNA and dsDNA, and less efficiently removes 5OHC and 5OHU from ssDNA. Unlike NEIL1/NEIL2, which perform β,δ-elimination, NEIL3 is mainly a monofunctional glycosylase acting via β-elimination only. The V2P mutant converts NEIL3 to a bifunctional mode, demonstrating that the N-terminal Val2 amino group is critical for monofunctional activity. Residue Lys81 is essential for catalysis. In vitro glycosylase/lyase assays; site-directed mutagenesis (V2P, K81 mutants); strand incision and base excision assays on ssDNA and dsDNA substrates DNA repair High 23755964
2013 Mouse Neil3 is the only mammalian glycosylase with excision activity on thymine glycol (Tg) in quadruplex DNA, and shows strong preference for Tg in telomeric sequence context. Neil3 and NEIL1 both excise Sp and Gh from quadruplex DNA. No glycosylase tested had activity on 8-oxoG in quadruplex DNA. In vitro glycosylase assays on quadruplex DNA substrates containing Tg, 8-oxoG, Gh, or Sp; comparison across five mammalian glycosylases (NEIL1, NEIL2, mNeil3, NTH1, OGG1) The Journal of biological chemistry High 23926102
2013 Crystal structure of mouse Neil3 glycosylase domain (MmuNeil3Δ324) at 2.0 Å resolution reveals the same overall Fpg/Nei fold but with distinct features: it lacks the αF-β9/10 loop that caps flipped-out 8-oxoG in bacterial Fpg (explaining inability to excise 8-oxoG), and it lacks void-filling residues while harboring negatively charged residues creating an unfavorable electrostatic environment for the opposite strand (explaining ssDNA preference). X-ray crystallography (2.0 Å crystal structure); structural comparison to Fpg/Nei homologs Structure (London, England : 1993) High 23313161
2017 NEIL3 co-localizes with TRF2 at telomeres during S phase via interaction with TRF1; this interaction enhances NEIL3 enzymatic activity. NEIL3 binds ssDNA via its intrinsically disordered C terminus in a telomere-sequence-independent manner. NEIL3 also interacts with APE1 and the long-patch BER proteins PCNA and FEN1. Loss of NEIL3 causes anaphase DNA bridging due to telomere dysfunction. Co-immunoprecipitation; co-localization by immunofluorescence with TRF2 and TRF1; in vitro enzymatic activity assay with TRF1; ssDNA binding assays; cell biology (anaphase bridge quantification in NEIL3 knockdown cells) Cell reports High 28854357
2020 In human cells, NEIL3 is recruited to psoralen-ICLs in a rapid, PARP-dependent manner and repairs them without generating DSBs. The RUVBL1/2 complex physically interacts with NEIL3 and functions within the NEIL3 pathway for psoralen-ICL repair. TRAIP promotes recruitment of NEIL3 (but not FANCD2) to ICLs and is non-epistatic with both NEIL3 and FA pathways, placing TRAIP upstream of both. The NEIL3 and FA/BRCA pathways are non-epistatic: NEIL3 is the primary pathway and FA/BRCA is activated only when NEIL3 is absent. Co-immunoprecipitation (NEIL3–RUVBL1/2); siRNA knockdown epistasis analysis; laser-induced damage recruitment assays; DSB quantification (γH2AX); ICL sensitivity assays Nucleic acids research High 31980815
2020 The tandem GRF-type zinc finger (Zf-GRF) domain of NEIL3 provides greater affinity and specificity for ssDNA than each individual motif alone. Crystal structure of the GRF domain shows a flexible head-to-tail configuration suited for binding multiple ssDNA conformations. Functionally, the NEIL3 GRF domain inhibits (autoinhibits) glycosylase activity against both monoadducts and ICLs, distinguishing it from other GRF-ZF domains that typically enhance catalytic activity. Crystal structure of GRF domain; ssDNA binding assays; glycosylase activity assays comparing full-length vs. truncated NEIL3; ICL unhooking assays The Journal of biological chemistry High 32878989
2022 Crystal structure of the NEIL3 tandem GRF zinc-finger domain bound to DNA, combined with a structure of the NEI catalytic domain in complex with a DNA reaction intermediate, enabled construction of a model explaining how the NEI and GRF domains cooperate to recognize an ICL at a DNA replication X-structure. The GRF domain preferentially binds replication fork structures. X-ray crystallography (GRF–DNA complex; NEI domain–DNA intermediate complex); biochemical ssDNA binding assays; structural modeling of ICL recognition Nucleic acids research High 36155818
2019 The glycosylase domain of murine NEIL3 (MmuNEIL3-GD) selectively unhooks dA-AP ICLs located at the duplex/single-strand junction of splayed duplexes modeling the leading template strand of a replication fork. NEIL3 preferentially acts on the AP residue on the leading template strand. The same strand preference applies to a 5,6-dihydrothymine monoadduct, showing it is a general feature of the glycosylase. Other BER enzymes (tested) do not unhook the dA-AP ICL. In vitro glycosylase/ICL unhooking assays on defined splayed-duplex fork substrates with site-specific dA-AP ICL or DHT monoadduct; comparison to other BER enzymes DNA repair High 31923807
2017 Human NEIL3 cleaves psoralen-induced ICLs in three-stranded and four-stranded DNA substrates, generating unhooked DNA fragments containing either an abasic site or a psoralen-thymine monoadduct, without generating single-strand breaks. This activity distinguishes NEIL3 from NEIL1/Nei, which nick the DNA during unhooking. In vitro glycosylase assays on defined three-stranded and four-stranded psoralen-crosslinked DNA substrates; product analysis by gel electrophoresis Scientific reports High 29234069
2022 NEIL3 promotes the HR step of FA/BRCA-pathway ICL repair (for MMC and cisplatin ICLs) through its GRF zinc finger motifs, which recruit NEIL3 to DSB sites and mediate interaction with the DSB resection machinery (CtIP, MRE11-RAD50-NBS1 complex, DNA2). NEIL3 depletion reduces chromatin recruitment of resection factors, decreases end resection, and compromises HR. Co-immunoprecipitation (NEIL3 with CtIP, MRN, DNA2); chromatin fractionation; HR reporter assay; end-resection assays (RPA/BrdU ssDNA); siRNA knockdown Cell reports High 36351389
2008 Human NEIL3 and its glycosylase domain (1-290) display AP lyase activity specific for ssDNA but not dsDNA. This activity is abolished by N-terminal deletion and by mutations at the zinc-finger motif. Expression of NEIL3 partially rescues an E. coli nth nei double mutant from hydrogen peroxide sensitivity. In vitro AP lyase assays on ssDNA/dsDNA; N-terminal deletion mutants; zinc-finger mutants; in vivo complementation of E. coli nth nei mutant Genes to cells : devoted to molecular & cellular mechanisms Medium 19170771
2012 Neil3 is the main DNA glycosylase responsible for incising hydantoin lesions in ssDNA in mouse tissues (demonstrated using total cell extracts from Neil3-/- mice). Loss of Neil3 impairs self-renewal of neural stem/progenitor cells (NSPCs) and reduces proliferation of mouse embryonic fibroblasts. Neil3-/- MEFs are sensitive to paraquat (oxidative stress) and cisplatin (ICL-inducing agent). Cell extracts from Neil3-/- mice in glycosylase activity assays; neurosphere culture (self-renewal assay); MEF proliferation assays; paraquat and cisplatin sensitivity assays Biochimica et biophysica acta Medium 23305905
2011 Neil3 knockout mice show reduced numbers of proliferating neuronal progenitors in the striatum and reduced neurogenesis after hypoxia-ischemia. Neil3-deficient neural stem/progenitor cells have reduced capacity to augment neurogenesis and reduced repair of oxidative base lesions in ssDNA. Neil3-/- mouse model; hypoxia-ischemia model; cell counting of neural progenitors; in vitro neurosphere expansion; ssDNA BER activity assays Proceedings of the National Academy of Sciences of the United States of America Medium 22065741
2012 Neil3-/- mice display learning/memory deficits and reduced anxiety-like behavior. Neural stem/progenitor cells from aged Neil3-/- mice show impaired proliferative capacity and reduced DNA repair activity (hydantoin excision in ssDNA). Hippocampal neurons in Neil3-/- mice display synaptic irregularities. Behavioral tests (learning/memory); neurosphere proliferation assays; glycosylase activity assays; synaptic morphology by electron microscopy in Neil3-/- mice Cell reports Medium 22959434
2005 Mouse NEIL3 protein localizes to the nucleus as demonstrated by immunofluorescence microscopy. Neil3 mRNA is selectively expressed in hematopoietic tissues (thymus, spleen, bone marrow) and is upregulated in splenocytes after mitogen stimulation in vitro. Immunofluorescence microscopy with anti-NEIL3 antibody on recombinant mouse NEIL3; Northern blot and RT-PCR for tissue expression; mitogen stimulation of splenocytes Journal of biochemistry Medium 16428305
2012 hNEIL3 expression is cell cycle regulated: it is repressed in quiescent cells (G0) and induced in early S phase upon mitogenic stimulation, under control of the Ras-dependent ERK-MAP kinase pathway. This regulation parallels that of the replication protein FEN1, suggesting a replication-associated repair function. Cell cycle synchronization; Western blot and qRT-PCR for hNEIL3 protein and mRNA levels; ERK pathway inhibitor experiments; comparison to hNEIL1 and hNEIL2 expression DNA repair Medium 22365498
2019 Human NEIL3 preferentially excises oxidized bases (5-hydroxyuracil, thymine glycol) from ssDNA and within open fork structures, while NEIL1 acts preferentially on dsDNA including damage upstream of the replication fork. Both enzymes act in concert at model replication fork substrates to remove oxidized bases from different structural contexts. In vitro glycosylase assays on model replication fork substrates with site-specific oxidized bases; comparison of NEIL1 and NEIL3 activity on ssDNA, dsDNA, and fork structures Genes Medium 31018584
2021 NEIL3 co-localizes with TRF2 and repairs oxidative DNA lesions at telomeres specifically during mitosis. NEIL3-depleted HCC cells accumulate oxidative DNA lesions at telomeres, leading to telomere dysfunctional foci and 53BP1 foci. Upon oxidative DNA damage during mitosis, NEIL3 relocates to telomeres and recruits APE1, and NEIL3 (but not NEIL1 or NEIL2) is required to initiate APE1- and POLB-dependent BER at oxidized telomeres. META-FISH; immunofluorescence co-localization; NEIL3 knockdown (siRNA/shRNA) with telomere damage quantification; co-localization of NEIL3 and APE1 at telomeres; comparison to NEIL1 and NEIL2 knockdown Cancer research Medium 34045188
2020 The NEIL3 Zf-GRF repeat (tandem, not single GRF motif) binds APE1 (but not APE2) via protein-protein interaction. This interaction suppresses APE1 endonuclease activity on ssDNA but not dsDNA, and excess NEIL3 Zf-GRF repeat reduces DNA damage in oxidative stress in Xenopus egg extracts. Protein-protein interaction assays (pull-down); APE1 endonuclease activity assays on ssDNA/dsDNA in presence of NEIL3 Zf-GRF; COMET assays in Xenopus egg extracts The Journal of biological chemistry Medium 32817342
2017 NEIL3 is required for PCNA- and FEN1-dependent long-patch BER at telomeres during S/G2 phase, and loss of NEIL3 causes anaphase DNA bridging due to telomere dysfunction; NEIL3 expression peaks in late S/G2 phase. Cell cycle synchronization and Western blot for NEIL3 levels; ChIP for telomere association; siRNA knockdown with anaphase bridge quantification; co-IP of NEIL3 with PCNA and FEN1 Cell reports Medium 28854357
2018 Mouse NEIL3 (MmuNEIL3Δ324) excises NM-Fapy-dG from ssDNA (but not dsDNA), while it cannot excise AFB1-Fapy-dG from either ssDNA or dsDNA. Product formation from ssDNA was incomplete and follows a single turnover rate of ~0.4 min-1. In vitro glycosylase assays on defined ssDNA and dsDNA oligonucleotides containing NM-Fapy-dG or AFB1-Fapy-dG; single turnover kinetics DNA repair Medium 30448017
2017 Loss of NEIL3 significantly increases spontaneous replication-associated DSBs and RPA recruitment, while decreasing Rad51 on nascent DNA at the replication fork, indicating that NEIL3 is required for HR-dependent repair at stalled forks. NEIL3 localizes to DSB sites during oxidative DNA damage and replication stress. NEIL3-deficient glioblastoma cells are sensitized to ATR inhibitor alone or combined with PARP1 inhibitor. NEIL3 knockdown (siRNA); γH2AX foci quantification; iPOND (isolation of proteins on nascent DNA) for Rad51 and RPA; ATR inhibitor sensitivity assays; immunofluorescence for NEIL3 at DSB sites Oncotarget Medium 29348879
2023 NEIL3 interacts with the 26S proteasome in a cisplatin-dependent manner (identified by proteomics) and mediates proteasomal degradation of WRNIP1, a protein involved in the early step of ICL repair. This facilitates a timely transition from lesion recognition to repair at ICL-stalled replication forks. Co-immunoprecipitation (NEIL3–26S proteasome); proteomic analysis; WRNIP1 degradation assay; gain- and loss-of-function experiments with cisplatin treatment Scientific reports Medium 36997601
2017 Loss of Neil3 in mice causes increased mortality after myocardial infarction due to myocardial rupture. Neil3-/- hearts show increased proliferation of fibroblasts and myofibroblasts post-MI. Genome-wide analysis reveals changes in 5mC and 5hmC in the cardiac epigenome, particularly in genes related to proliferation and myofibroblast differentiation, suggesting NEIL3-dependent modulation of DNA methylation regulates cardiac fibroblast behavior. Neil3-/- mouse MI model; survival analysis; histology; genome-wide 5mC/5hmC profiling; fibroblast proliferation quantification Cell reports Medium 28052262
2022 Neil3 deficiency in VSMCs promotes a shift towards a proliferating, lipid-accumulating, secretory macrophage-like phenotype (transdifferentiation) associated with increased Akt signaling pathway activity. NEIL3-abrogated human primary aortic VSMCs show Akt-dependent proliferation. These effects occur without changes in DNA damage levels, suggesting a non-canonical role for NEIL3 in VSMC phenotype regulation. Neil3-/- Apoe-/- mouse model; siRNA knockdown of NEIL3 in human primary aortic VSMCs; BrdU proliferation assay; Western blot for Akt phosphorylation; Akt inhibitor experiments; single-cell RNA sequencing and proteomics Atherosclerosis Medium 33714552
2022 NEIL3 directly interacts with the EMT transcription factor TWIST1 and induces transcription of MDR1 (ABCB1) and BRAF genes through E-box promoter elements recognized by TWIST1, leading to BRAF/MEK/ERK pathway-mediated cell proliferation and drug resistance in HCC. Co-immunoprecipitation (NEIL3–TWIST1); RNA-seq; invasion/migration assays; mouse orthotopic HCC model; BRAF/MEK/ERK pathway analysis by Western blot; promoter reporter assays The Journal of pathology Medium 36181299
2022 E2F1 transcriptionally activates NEIL3 expression, and NEIL3 overexpression in turn activates the cyclin D1-Rb-E2F1 pathway, forming a positive feedback loop that promotes cell proliferation and cell cycle progression in clear cell renal cell carcinoma. ChIP; luciferase reporter assay; siRNA/overexpression experiments; Western blot; cell proliferation and cell cycle assays; in vivo xenograft DNA repair Low 37992567
2022 SNHG3 increases E2F1 binding to the NEIL3 promoter region, thereby activating NEIL3 transcription in hepatocellular carcinoma cells. NEIL3 participates in SNHG3-mediated regulation of HCC cell cycle, apoptosis, and proliferation (rescue experiments). ChIP assay (E2F1 binding to NEIL3 promoter); luciferase reporter; siRNA knockdown of SNHG3; rescue experiments with NEIL3 overexpression; CCK-8; flow cytometry Immunogenetics Low 36114381
2025 NEIL3 deficiency leads to reduced PV+ GABAergic interneurons, impaired perineuronal net (PNN) integrity, altered hippocampal oscillatory dynamics (increased beta and low gamma power; reduced high gamma and ripple activity), and distinct effects on contextual vs. trace fear memory. Transcriptomic analysis reveals dysregulation of glutamatergic/GABAergic signaling genes, including Gabra2 downregulation potentially driven by changes in promoter DNA methylation. Neil3-/- mouse model; immunofluorescence (PV+ interneuron counting); PNN staining; in vivo electrophysiology (hippocampal oscillations); fear conditioning behavioral paradigms; RNA sequencing; bisulfite sequencing (DNA methylation) Progress in neurobiology Low 41015225
2025 NEIL3 deficiency impairs adult hippocampal neurogenesis and behavioral pattern separation through altered transcriptional regulation of the Wnt signaling pathway, not through decreased genomic integrity. NEIL3-deficient adult-born neurons show reduced mature-like membrane properties. Neil3-/- mouse model; neurosphere proliferation and differentiation assays; behavioral pattern separation tests; electrophysiology of adult-born neurons; RNA sequencing; Wnt pathway inhibitor experiments Cellular and molecular life sciences : CMLS Low 40035863

Source papers

Stage 0 corpus · 67 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 Replication-Dependent Unhooking of DNA Interstrand Cross-Links by the NEIL3 Glycosylase. Cell 174 27693351
2010 The mouse ortholog of NEIL3 is a functional DNA glycosylase in vitro and in vivo. Proceedings of the National Academy of Sciences of the United States of America 172 20185759
2013 Neil3 and NEIL1 DNA glycosylases remove oxidative damages from quadruplex DNA and exhibit preferences for lesions in the telomeric sequence context. The Journal of biological chemistry 114 23926102
2013 Human NEIL3 is mainly a monofunctional DNA glycosylase removing spiroimindiohydantoin and guanidinohydantoin. DNA repair 82 23755964
2012 Neil3, the final frontier for the DNA glycosylases that recognize oxidative damage. Mutation research 80 23274422
2011 Endonuclease VIII-like 3 (Neil3) DNA glycosylase promotes neurogenesis induced by hypoxia-ischemia. Proceedings of the National Academy of Sciences of the United States of America 78 22065741
2012 Hippocampal adult neurogenesis is maintained by Neil3-dependent repair of oxidative DNA lesions in neural progenitor cells. Cell reports 74 22959434
2009 Expression patterns of Neil3 during embryonic brain development and neoplasia. BMC neuroscience 68 19426544
2017 NEIL3 Repairs Telomere Damage during S Phase to Secure Chromosome Segregation at Mitosis. Cell reports 66 28854357
2016 Deficiency of base excision repair enzyme NEIL3 drives increased predisposition to autoimmunity. The Journal of clinical investigation 65 27760045
2020 Cooperation of the NEIL3 and Fanconi anemia/BRCA pathways in interstrand crosslink repair. Nucleic acids research 64 31980815
2005 Hematopoietic tissue-specific expression of mouse Neil3 for endonuclease VIII-like protein. Journal of biochemistry 57 16428305
2017 NEIL3-Dependent Regulation of Cardiac Fibroblast Proliferation Prevents Myocardial Rupture. Cell reports 50 28052262
2013 Structural characterization of a mouse ortholog of human NEIL3 with a marked preference for single-stranded DNA. Structure (London, England : 1993) 50 23313161
2016 Abnormal Expressions of DNA Glycosylase Genes NEIL1, NEIL2, and NEIL3 Are Associated with Somatic Mutation Loads in Human Cancer. Oxidative medicine and cellular longevity 46 27042257
2012 Release from quiescence stimulates the expression of human NEIL3 under the control of the Ras dependent ERK-MAP kinase pathway. DNA repair 46 22365498
2008 Human Nei-like protein NEIL3 has AP lyase activity specific for single-stranded DNA and confers oxidative stress resistance in Escherichia coli mutant. Genes to cells : devoted to molecular & cellular mechanisms 43 19170771
2019 The Biochemical Role of the Human NEIL1 and NEIL3 DNA Glycosylases on Model DNA Replication Forks. Genes 38 31018584
2017 A role for the base excision repair enzyme NEIL3 in replication-dependent repair of interstrand DNA cross-links derived from psoralen and abasic sites. DNA repair 36 28262582
2012 Expression and purification of active mouse and human NEIL3 proteins. Protein expression and purification 36 22569481
2013 Loss of Neil3, the major DNA glycosylase activity for removal of hydantoins in single stranded DNA, reduces cellular proliferation and sensitizes cells to genotoxic stress. Biochimica et biophysica acta 35 23305905
2017 The Human DNA glycosylases NEIL1 and NEIL3 Excise Psoralen-Induced DNA-DNA Cross-Links in a Four-Stranded DNA Structure. Scientific reports 34 29234069
2019 Unhooking of an interstrand cross-link at DNA fork structures by the DNA glycosylase NEIL3. DNA repair 33 31923807
2017 Loss of NEIL3 DNA glycosylase markedly increases replication associated double strand breaks and enhances sensitivity to ATR inhibitor in glioblastoma cells. Oncotarget 29 29348879
2021 Loss of NEIL3 activates radiotherapy resistance in the progression of prostate cancer. Cancer biology & medicine 28 34591415
2016 Neil3-dependent base excision repair regulates lipid metabolism and prevents atherosclerosis in Apoe-deficient mice. Scientific reports 25 27328939
2018 The Fifth Domain in the G-Quadruplex-Forming Sequence of the Human NEIL3 Promoter Locks DNA Folding in Response to Oxidative Damage. Biochemistry 24 29718661
2012 The DNA glycosylases OGG1 and NEIL3 influence differentiation potential, proliferation, and senescence-associated signs in neural stem cells. Biochemical and biophysical research communications 24 22564741
2008 Expression and purification of NEIL3, a human DNA glycosylase homolog. Protein expression and purification 24 19121397
2021 NEIL3 Prevents Senescence in Hepatocellular Carcinoma by Repairing Oxidative Lesions at Telomeres during Mitosis. Cancer research 23 34045188
2021 Phase I studies of peptide vaccine cocktails derived from GPC3, WDRPUH and NEIL3 for advanced hepatocellular carcinoma. Immunotherapy 22 33525928
2021 Deficiency of NEIL3 Enhances the Chemotherapy Resistance of Prostate Cancer. International journal of molecular sciences 21 33921035
2021 NEIL3 contributes toward the carcinogenesis of liver cancer and regulates PI3K/Akt/mTOR signaling. Experimental and therapeutic medicine 21 34434267
2016 Neil3 induced neurogenesis protects against prion disease during the clinical phase. Scientific reports 21 27886261
2015 Genetic variants in the DNA repair gene NEIL3 and the risk of myocardial infarction in a nested case-control study. The HUNT Study. DNA repair 21 25703835
2020 An autoinhibitory role for the GRF zinc finger domain of DNA glycosylase NEIL3. The Journal of biological chemistry 20 32878989
2018 Processing of N5-substituted formamidopyrimidine DNA adducts by DNA glycosylases NEIL1 and NEIL3. DNA repair 18 30448017
2022 Biological Functions of the DNA Glycosylase NEIL3 and Its Role in Disease Progression Including Cancer. Cancers 17 36497204
2020 A non-canonical role for the DNA glycosylase NEIL3 in suppressing APE1 endonuclease-mediated ssDNA damage. The Journal of biological chemistry 17 32817342
2022 SNHG3 regulates NEIL3 via transcription factor E2F1 to mediate malignant proliferation of hepatocellular carcinoma. Immunogenetics 16 36114381
2022 NEIL3 promotes hepatoma epithelial-mesenchymal transition by activating the BRAF/MEK/ERK/TWIST signaling pathway. The Journal of pathology 16 36181299
2021 DNA glycosylase Neil3 regulates vascular smooth muscle cell biology during atherosclerosis development. Atherosclerosis 16 33714552
2024 NEIL3: A unique DNA glycosylase involved in interstrand DNA crosslink repair. DNA repair 14 38663144
2022 NEIL3 Mediates Lung Cancer Progression and Modulates PI3K/AKT/mTOR Signaling: A Potential Therapeutic Target. International journal of genomics 14 35535347
2024 Transcription Factor MAZ Potentiates the Upregulated NEIL3-mediated Aerobic Glycolysis, thereby Promoting Angiogenesis in Hepatocellular Carcinoma. Current cancer drug targets 13 38347781
2022 Model of abasic site DNA cross-link repair; from the architecture of NEIL3 DNA binding domains to the X-structure model. Nucleic acids research 12 36155818
2016 Single nucleotide polymorphisms in the REG-CTNNA2 region of chromosome 2 and NEIL3 associated with impulsivity in a Native American sample. Genes, brain, and behavior 12 27167163
2023 Transcriptional factor MAZ promotes cisplatin-induced DNA damage repair in lung adenocarcinoma by regulating NEIL3. Pulmonary pharmacology & therapeutics 11 37121465
2022 NEIL3 contributes to the Fanconi anemia/BRCA pathway by promoting the downstream double-strand break repair step. Cell reports 11 36351389
2018 Identification of retinal homeobox (rax) gene-dependent genes by a microarray approach: The DNA endoglycosylase neil3 is a major downstream component of the rax genetic pathway. Developmental dynamics : an official publication of the American Association of Anatomists 9 30311321
2024 NEIL3 Upregulated by TFAP2A Promotes M2 Polarization of Macrophages in Liver Cancer via the Mediation of Glutamine Metabolism. Digestion 8 39342941
2022 NEIL3-deficient bone marrow displays decreased hematopoietic capacity and reduced telomere length. Biochemistry and biophysics reports 8 35079641
2021 DNA repair enzyme NEIL3 enables a stable neural representation of space by shaping transcription in hippocampal neurons. iScience 8 34988395
2023 NEIL3-mediated proteasomal degradation facilitates the repair of cisplatin-induced DNA damage in human cells. Scientific reports 7 36997601
2022 Age- and sex-dependent effects of DNA glycosylase Neil3 on amyloid pathology, adult neurogenesis, and memory in a mouse model of Alzheimer's disease. Free radical biology & medicine 6 36395955
2025 NEIL3 influences adult neurogenesis and behavioral pattern separation via WNT signaling. Cellular and molecular life sciences : CMLS 5 40035863
2024 Novel Processes Associated with the Repair of Interstrand Cross-Links Derived from Abasic Sites in Duplex DNA: Roles for the Base Excision Repair Glycosylase NEIL3 and the SRAP Protein HMCES. Chemical research in toxicology 5 38198604
2023 NEIL3 promoter G-quadruplex with oxidatively modified bases shows magnesium-dependent folding that stalls polymerase bypass. Biochimie 5 37437684
2021 NEIL3-deficiency increases gut permeability and contributes to a pro-atherogenic metabolic phenotype. Scientific reports 5 34611194
2022 WT1 regulates expression of DNA repair gene Neil3 during nephrogenesis. American journal of physiology. Renal physiology 4 36546838
2022 Pan-Cancer Landscape of NEIL3 in Tumor Microenvironment: A Promising Predictor for Chemotherapy and Immunotherapy. Cancers 4 36612106
2023 NEIL3 promotes cell proliferation of ccRCC via the cyclin D1-Rb-E2F1 feedback loop regulation. DNA repair 2 37992567
2025 NEIL3 promotes the carcinogenesis of prostate cancer by activating PI3K/Akt/mTOR signaling. Discover oncology 1 40447877
2025 NEIL3 and TOP2A as key drivers of esophageal cancer through WNT signaling. Biomolecules & biomedicine 0 39910812
2025 NEIL3 Deficiency Enhances HCC Cell Sensitivity to Oxaliplatin by Inhibiting the Fanconi Anaemia Pathway. Cell biology international 0 40263742
2025 FOXM1 transcriptionally activates NEIL3 to inhibit ferroptosis in lung adenocarcinoma cells. Journal of clinical biochemistry and nutrition 0 40777817
2025 NEIL3 shapes hippocampal network dynamics and fear memory through modulation of PV+ interneurons. Progress in neurobiology 0 41015225

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