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GADD45A

Growth arrest and DNA damage-inducible protein GADD45 alpha · UniProt P24522

Length
165 aa
Mass
18.3 kDa
Annotated
2026-06-09
100 papers in source corpus 39 papers cited in narrative 39 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 7/8 claims corpus-supported (88%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GADD45A is a stress-inducible nuclear protein that couples genotoxic and metabolic stress signals to cell cycle arrest, genome maintenance, and epigenetic remodeling (PMID:1423616, PMID:10508513). It is transcriptionally activated by p53 binding to a conserved third-intron element following ionizing radiation, integrating an ATM→p53→GADD45A DNA-damage checkpoint cascade (PMID:1423616), and is additionally driven by BRCA1 (via Oct-1/NF-YA at the promoter), FOXO3a, an intronic AP-1/JunD element, and ATF4 in skeletal muscle (PMID:11777930, PMID:11964479, PMID:17084916, PMID:22692209). The protein acts as a multivalent adapter: it binds PCNA through its C-terminus and stimulates nucleotide and base excision repair while restraining S-phase entry (PMID:7973727, PMID:7478510, PMID:17599061), and it directly binds and inhibits Cdc2 via a central domain (aa 65–84), dissociating the Cdc2-cyclin B1 complex and driving Cdc2 nuclear export to enforce the G2/M checkpoint (PMID:10747892, PMID:10097101, PMID:12164919). GADD45A safeguards genomic stability—its loss causes aneuploidy and centrosome amplification—in part by inhibiting Aurora-A kinase and cooperating with BRCA1 to regulate NEK2 (PMID:10508513, PMID:16772293, PMID:15123655). A second major role is locus-specific active DNA demethylation: GADD45A binds R-loops at CpG island promoters and recruits TET1 and TDG to drive oxidative demethylation, an activity guided by lncRNA scaffolds (TARID), H3K4me3/Ing1, and an RNA-binding/chromatin-relaxing function requiring residue G39 (PMID:30617255, PMID:25087872, PMID:25845601, PMID:26546041, PMID:23388825, PMID:27702986, PMID:17268471). GADD45A self-oligomerizes and is escorted to the nucleus by nucleophosmin/B23 (PMID:11498536, PMID:15644315). Beyond the nucleus it triggers EF-1α-dependent apoptosis, inhibits autophagy by dissociating BECN1 from PIK3C3, suppresses tumor angiogenesis by disrupting the mTOR-STAT3-VEGF axis, and drives skeletal muscle atrophy through activation of MEKK4 (MAP3K4) (PMID:15899854, PMID:26636486, PMID:23329839, PMID:27358404). Its downstream output is cell-context-dependent, signaling largely through p38 MAPK to promote differentiation in hematopoietic stem cells rather than arrest or death (PMID:26731607, PMID:16636063).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 1992 High

    Established how DNA damage is transduced to a transcriptional output, placing GADD45A as a direct p53 effector in the G1 checkpoint cascade.

    Evidence EMSA of p53 binding to a third-intron element plus reporter assays and genetic epistasis in p53-null and AT cells

    PMID:1423616

    Open questions at the time
    • Does not establish the protein's biochemical activity
    • Other inducers (BRCA1, FOXO3a, AP-1) not yet identified
  2. 1994 High

    Defined GADD45A's first molecular partner and activity, linking it to DNA repair and S-phase restraint through PCNA binding.

    Evidence Co-IP, in vitro excision repair assay, and cell cycle analysis

    PMID:7973727

    Open questions at the time
    • Interaction interface on either protein not mapped
    • Mechanism of S-phase inhibition unresolved
  3. 1995 High

    Resolved how GADD45A competes within the PCNA-p21 axis, showing it binds p21 and disrupts PCNA trimers in a repair-dependent manner.

    Evidence Co-IP, ELISA peptide binding, yeast two-hybrid, Far-western with recombinant protein, cell synchronization

    PMID:7478510 PMID:7478594

    Open questions at the time
    • Functional consequence of PCNA trimer disruption for replication vs repair not separated
  4. 1999 High

    Mapped GADD45A onto the G2/M checkpoint and chromatin, and clarified that it is downstream—not upstream—of stress kinases.

    Evidence Microinjection/flow cytometry, gadd45-/- and antisense cells, core histone and mononucleosome binding assays, JNK/p38 kinase assays in knockout MEFs

    PMID:10022855 PMID:10097101 PMID:10514426

    Open questions at the time
    • Direct Cdc2-binding domain not yet defined
    • Histone-binding interface unmapped
  5. 1999 High

    Identified BRCA1 as an inducer and demonstrated in vivo that GADD45A loss produces genomic instability and increased carcinogenesis, validating its tumor-suppressor role.

    Evidence Inducible BRCA1 expression with expression arrays and JNK assays; gadd45a-/- mice with cytogenetic and carcinogenesis analysis

    PMID:10367887 PMID:10508513

    Open questions at the time
    • Molecular basis linking GADD45A loss to centrosome amplification not yet defined
  6. 2000 High

    Pinpointed the exact Cdc2-binding domain (aa 65–84) and showed it is required for checkpoint and growth suppression, and that GADD45A self-oligomerizes.

    Evidence Deletion mutants, peptide library, in vitro/in vivo co-IP, kinase and colony assays; gel filtration, native gels, cross-linking

    PMID:10747892 PMID:11498536

    Open questions at the time
    • Functional role of oligomerization state not established
    • Stoichiometry of Cdc2-cyclin B1 dissociation unresolved
  7. 2002 High

    Detailed transcriptional control of GADD45A by BRCA1-Oct1-NF-YA and by FOXO3a, embedding it in BRCA1 and PI3K-Akt-FOXO signaling.

    Evidence Promoter mutagenesis, reporter, pull-down, ChIP; FOXO3a gene array and functional epistasis

    PMID:11777930 PMID:11964479

    Open questions at the time
    • Relative contribution of each input in different stresses unquantified
  8. 2002 Medium

    Connected GADD45A's checkpoint function to NER and Cdc2 nuclear export, and to a positive feedback loop stabilizing p53.

    Evidence Cdc2 kinase/localization assays and NER in gadd45-/- keratinocytes; p53 stabilization in gadd45a-/- MEFs with p38 inhibitor

    PMID:12164919 PMID:14627995

    Open questions at the time
    • Direct mechanism of p53 Ser-15 phosphorylation by GADD45A not established
  9. 2003 Medium

    Expanded the cell cycle inhibitory module by identifying CRIF1 as a cooperating partner inhibiting Cdc2 and Cdk2 complexes.

    Evidence GST pull-down, co-IP, mammalian two-hybrid, histone H1 kinase assay

    PMID:12716909

    Open questions at the time
    • Single lab; physiological role of CRIF1-GADD45A complex untested in vivo
  10. 2004 High

    Explained the centrosome stability phenotype mechanistically through BRCA1/GADD45A regulation of NEK2 and direct inhibition of Aurora-A kinase.

    Evidence siRNA/overexpression epistasis in gadd45a-/- MEFs with centrosome counting; co-IP, Aurora-A kinase assay, and rescue

    PMID:15123655 PMID:16772293

    Open questions at the time
    • Aurora-A inhibition mechanism (substrate vs allosteric) not defined
  11. 2005 Medium

    Established cytoplasmic apoptotic and nuclear-import roles via EF-1α (Bim/Bax axis) and B23/nucleophosmin-mediated nuclear translocation.

    Evidence Co-IP with EF-1α, cytochrome c fractionation, Bim siRNA, domain mutants; B23 co-IP, deletion mapping (aa 61–100), siRNA, localization

    PMID:15644315 PMID:15899854

    Open questions at the time
    • Single-lab findings without reciprocal in vivo validation
    • Apoptotic vs arrest decision determinants unresolved
  12. 2006 Medium

    Distinguished GADD45A as a pro-survival/differentiation signal via p38-NF-kB and an intronic AP-1/JunD transcriptional input.

    Evidence gadd45a-/- and gadd45b-/- bone marrow with inhibitors and reconstitution; intron reporter mutagenesis, EMSA, JunD ChIP

    PMID:16636063 PMID:17084916

    Open questions at the time
    • How p38 output is routed to survival vs arrest not mechanistically resolved
  13. 2007 High

    Opened a new functional axis by showing GADD45A drives active DNA demethylation, requiring repair machinery (XPG), and acts as a non-enzymatic facilitator coupling deaminase/glycosylase activities.

    Evidence Reporter demethylation, siRNA, Xenopus oocyte injection, XPG co-IP, bisulfite sequencing; zebrafish morpholino with AID/Mbd4 coupling assay

    PMID:17268471 PMID:19109892

    Open questions at the time
    • Locus-specificity mechanism not yet explained
    • Direct GADD45A nucleic-acid binding not yet defined
  14. 2007 Medium

    Extended GADD45A function to cell-cell adhesion and BER, acting as a beta-catenin/Caveolin-1 adapter and as a regulator of APE1 localization.

    Evidence Co-IP, fractionation, p38 inhibitor for beta-catenin; BER assay, APE1 localization, APE1-PCNA co-IP in gadd45a-/- cells

    PMID:17452974 PMID:17599061

    Open questions at the time
    • Single-lab observations; direct vs indirect effect on APE1 localization unclear
  15. 2011 Medium

    Identified GADD45A as an RNA-binding protein localized to nuclear speckles, providing a biochemical basis for its demethylation targeting.

    Evidence In vitro RNA-binding assay, sucrose gradients, RNase-sensitive colocalization with p68/SC35, G39A/K45A mutations

    PMID:21249130

    Open questions at the time
    • RNA species recognized in vivo not identified
    • Single lab
  16. 2012 High

    Defined a distinct physiological program in which ATF4-induced GADD45A is necessary and sufficient for skeletal muscle atrophy.

    Evidence ATF4 muscle KO, GADD45A gain/loss across fasting, immobilization, denervation models, expression profiling

    PMID:22692209

    Open questions at the time
    • Downstream effector kinase not yet identified at this stage
  17. 2013 Medium

    Revealed cytoplasmic/metabolic functions: anti-angiogenic disruption of the mTOR-STAT3-VEGF axis and chromatin targeting of demethylation by Ing1/H3K4me3.

    Evidence Co-IP with mTOR/STAT3, phospho-STAT3 blot, VEGF ELISA, CAM assay; ChIP, co-IP, H3K4me manipulation with reporter demethylation

    PMID:23329839 PMID:23388825

    Open questions at the time
    • Whether mTOR association is direct unresolved
    • Histone-mark reading mechanism by GADD45A/Ing1 incomplete
  18. 2014 High

    Assembled a defined lncRNA-GADD45A-TDG demethylation chain, linking RNA scaffolding to TET-coupled base excision repair.

    Evidence RIP, ChIP, GADD45A-TDG co-IP, bisulfite sequencing, reporter demethylation

    PMID:25087872

    Open questions at the time
    • General applicability beyond TCF21 locus not established at this point
  19. 2015 High

    Mechanistically integrated GADD45A into TET-TDG oxidative demethylation, enhancing excision of 5fC/5caC, with genetic confirmation in ES cells.

    Evidence GADD45A-TDG and GADD45A-TET1 co-IP, reporter assays with active enzymes, 5fC/5caC quantification, Gadd45a/b double-KO ES cells, siRNA epistasis

    PMID:25845601 PMID:26546041

    Open questions at the time
    • Stoichiometry and order of TET1/TDG recruitment unresolved
  20. 2015 Medium

    Identified an autophagy-regulatory role: GADD45A dissociates the BECN1-PIK3C3 complex via aa 71–81 to suppress autophagosome initiation.

    Evidence Co-IP, GST pull-down, domain mapping, LC3-II blot, autophagosome counting, BECN1 siRNA epistasis

    PMID:26636486

    Open questions at the time
    • Single lab; physiological context of autophagy suppression untested in vivo
  21. 2016 High

    Resolved the effector for muscle atrophy (MEKK4/MAP3K4 activation) and established GADD45A as a chromatin relaxer enhancing reprogramming, plus a p38-driven differentiation role in HSCs.

    Evidence In vivo GADD45A-MEKK4 complex isolation and kinase assay with necessity/sufficiency tests; FRAP, histone co-IP, G39 mutation, reprogramming and Yamanaka-factor ChIP; HSC live imaging, transplantation, p38 analysis

    PMID:26731607 PMID:27358404 PMID:27702986

    Open questions at the time
    • How GADD45A switches between MEKK4, p38, and chromatin outputs is unresolved
  22. 2019 High

    Unified the demethylation model genome-wide by showing GADD45A directly binds R-loops at CpG islands to recruit TET1, defining R-loop-dependent demethylation sites.

    Evidence DRIP-seq, GADD45A and TET1 ChIP-seq, in vitro R-loop binding, RNase H1 depletion, bisulfite sequencing, co-IP

    PMID:30617255

    Open questions at the time
    • Determinants of which R-loops are bound not fully defined
    • Link between R-loop binding and checkpoint functions unexplored

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single small adapter selects among its many mutually exclusive outputs—checkpoint enforcement, demethylation, apoptosis, autophagy suppression, and MEKK4/p38 signaling—in a tissue- and stress-specific manner remains unresolved.
  • No structural model integrating its multiple binding interfaces
  • Mechanism routing GADD45A toward one partner over another is unknown
  • Post-translational regulation governing partner choice uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0060090 molecular adaptor activity 4 GO:0140110 transcription regulator activity 3 GO:0003723 RNA binding 2 GO:0042393 histone binding 2
Localization
GO:0005634 nucleus 3 GO:0005694 chromosome 3 GO:0005829 cytosol 3 GO:0005654 nucleoplasm 2
Pathway
R-HSA-4839726 Chromatin organization 4 R-HSA-1640170 Cell Cycle 3 R-HSA-73894 DNA Repair 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-9612973 Autophagy 1
Partners
AURKABECN1CDK1MAP3K4MTORPCNATDGTET1

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 p53 binds directly to a conserved element in the third intron of the GADD45A gene to activate its transcription following ionizing radiation; this pathway (ATM gene(s) → p53 → GADD45A) constitutes a DNA damage-induced G1 cell cycle checkpoint signaling cascade. EMSA (p53 binding to GADD45 intronic element), functional reporter assays, genetic epistasis using p53-null fibroblasts and AT cells Cell High 1423616
1994 GADD45A protein binds directly to PCNA (proliferating cell nuclear antigen), stimulates DNA excision repair in vitro, and inhibits entry of cells into S phase. Co-immunoprecipitation, in vitro DNA excision repair assay, cell cycle analysis Science High 7973727
1995 GADD45A directly interacts with p21Cip1 as shown by co-immunoprecipitation from mammalian cells, ELISA with overlapping p21 peptides, and yeast two-hybrid assay; GADD45A protein levels are highest in G1 and are reduced during S phase. Co-immunoprecipitation, ELISA peptide-binding assay, yeast two-hybrid, cell synchronization/Western blot Oncogene High 7478594
1995 GADD45A directly binds PCNA via Far-western blotting (using 32P-labeled recombinant GADD45A); GADD45A and p21 competitively bind PCNA; GADD45A partially disrupts PCNA trimers and PCNA trimer disruption occurs in UV-irradiated cells but not XP-A repair-defective cells. Far-western blotting with purified recombinant proteins, co-immunoprecipitation, immunoblotting Oncogene High 7478510
1999 GADD45A induces G2/M cell cycle arrest by modulating cyclin B1/Cdc2 (p34cdc2) kinase activity; overexpression of cyclin B1 or Cdc25C inhibits GADD45A-mediated G2/M arrest; GADD45A-deficient cells show impaired G2/M checkpoint after UV or MMS exposure. Microinjection of expression vector into primary fibroblasts, flow cytometry, genetic epistasis using GADD45A antisense and gadd45-/- knockout mice, overexpression of cyclin B1/Cdc25C PNAS High 10097101
1999 GADD45A protein directly associates with all four core histones and can modulate DNA accessibility on damaged chromatin; it facilitates topoisomerase relaxing and cleavage activity in the presence of core histones; it directly associates with mononucleosomes altered by histone acetylation or UV radiation. Direct binding assays with core histones, mononucleosome binding assays, DNase I accessibility assays, T4 endonuclease V accessibility assay Molecular and Cellular Biology Medium 10022855
1999 GADD45A is not required for activation of JNK or p38 kinases during acute genotoxic stress; JNK/p38 activation significantly precedes GADD45A induction and is unimpaired in gadd45-/- fibroblasts. Kinase activity assays in gadd45-null mouse embryonic fibroblasts treated with MMS, H2O2, UVC, sorbitol, and anisomycin Journal of Biological Chemistry Medium 10514426
1999 BRCA1 inducible expression transcriptionally upregulates GADD45A, and BRCA1-induced apoptosis is linked to activation of the JNK/SAPK pathway in a p53-independent manner involving GADD45A. Inducible BRCA1 expression cell lines, high-density oligonucleotide arrays for gene expression profiling, JNK/SAPK activity assays Cell Medium 10367887
1999 Gadd45a-null mice exhibit genomic instability (aneuploidy, chromosome aberrations, gene amplification, centrosome amplification), abnormal mitosis, and increased radiation carcinogenesis, phenocopying aspects of p53-deficiency. Gene-targeting to generate gadd45a-/- mice; cytogenetic analysis, centrosome counting, carcinogenesis assays Nature Genetics High 10508513
2000 GADD45A inhibits Cdc2 kinase activity through a central domain (amino acids 65–84) that directly binds Cdc2; this binding disrupts the Cdc2-cyclin B1 protein complex; deletion of the Cdc2-binding motif abolishes GADD45A-induced G2/M arrest and growth suppression. Myc-tagged deletion mutants, overlapping peptide library, in vitro and in vivo co-immunoprecipitation, kinase activity assays, colony formation assays Journal of Biological Chemistry High 10747892
2000 GADD45A (and MyD118/Gadd45b) interact with PCNA via N-terminal (1–46) and middle (100–127) regions of PCNA, while the PCNA-interacting domain on GADD45A maps to its C-terminus (amino acids 137–165); interaction with PCNA impedes GADD45A-mediated negative growth control and apoptosis. GST pull-down, co-immunoprecipitation, ectopic expression of deletion mutants, colony formation and apoptosis assays Journal of Biological Chemistry Medium 10828065
2001 GADD45A self-associates to form dimers, trimers, and tetramers (predominantly dimers) in vitro and in cells; it can also hetero-complex with Gadd45b and Gadd45g; two self-association sites are mapped within N-terminal aa 33–61 and C-terminal 40 aa; oligomerization may modulate DNA accessibility on damaged nucleosomes. Gel-exclusion chromatography, native gel electrophoresis, ELISA, chemical cross-linking, deletion mutant and peptide scanning analyses Journal of Biological Chemistry Medium 11498536
2002 BRCA1 activates the GADD45A promoter through OCT-1 and CAAT motifs by physically associating with transcription factors Oct-1 and NF-YA; immunodepletion of Oct-1 or NF-YA or mutations in these motifs disrupt BRCA1 binding to the GADD45A promoter. Site-directed mutagenesis of promoter elements, reporter assays, biotin-streptavidin pull-down, co-immunoprecipitation, chromatin immunoprecipitation Journal of Biological Chemistry High 11777930
2002 GADD45A promotes G2/M arrest by inducing nuclear export of Cdc2 and inhibiting its kinase activity; Gadd45a-deficient keratinocytes show reduced nucleotide excision repair rate and increased UV sensitivity. Cell cycle analysis, Cdc2 kinase assay in immunoprecipitates, immunofluorescence for Cdc2 localization, NER repair assay in gadd45-/- keratinocytes Journal of Investigative Dermatology Medium 12164919
2002 FOXO3a directly regulates GADD45A transcription as a target gene, mediating FOXO3a's G2-M checkpoint function and DNA repair response; this acts downstream of the PI3K-Akt pathway. Gene array analysis for FOXO3a targets, functional assays for G2-M checkpoint and DNA repair, epistasis with FOXO3a and GADD45A Science Medium 11964479
2003 GADD45A interacts with CR6-interacting factor 1 (CRIF1) in vitro (GST pull-down) and in vivo (co-IP and mammalian two-hybrid); CRIF1 additively inhibits Cdc2-cyclin B1 and Cdk2-cyclin E histone H1 kinase activity together with GADD45A. GST pull-down, co-immunoprecipitation, mammalian two-hybrid, histone H1 kinase assay Journal of Biological Chemistry Medium 12716909
2003 GADD45A contributes to p53 stabilization after UVB via p38 kinase; Gadd45a-/- MEFs show greatly reduced p53 protein stabilization and Ser-15 phosphorylation after UVB; inducible GADD45A enhances p53 accumulation after UVB, defining a positive feedback loop upstream of p53. Gadd45a-/- mouse embryonic fibroblasts, Western blot for p53 and phospho-p53, p38 kinase inhibitor, inducible GADD45A expression Oncogene Medium 14627995
2004 BRCA1 and GADD45A cooperatively regulate NEK2 transcription; siRNA knockdown of BRCA1 decreases Nek2 more dramatically in Gadd45a-/- cells; overexpression of either BRCA1 or GADD45A upregulates NEK2; overexpression of NEK2 suppresses centrosome amplification caused by BRCA1 knockdown. siRNA knockdown, overexpression, epistasis in Gadd45a-/- MEFs, centrosome counting Journal of Biological Chemistry Medium 15123655
2005 GADD45A induces apoptosis by interacting with elongation factor 1α (EF-1α), inhibiting EF-1α-mediated microtubule bundling, thereby causing Bim dissociation from microtubule-associated components and translocation to mitochondria; Bim accumulation at mitochondria releases Bax from Bcl-2, triggering cytochrome c release. Inducible expression of GADD45A, co-immunoprecipitation (EF-1α interaction), cytochrome c fractionation, siRNA knockdown of Bim, GADD45A deletion mutant lacking EF-1α-binding domain Molecular and Cellular Biology Medium 15899854
2005 B23/nucleophosmin directly associates with GADD45A and mediates its nuclear translocation; the B23-interacting domain maps to aa 61–100 of GADD45A; siRNA knockdown of B23 disrupts GADD45A nuclear localization and impairs GADD45A-induced G2/M arrest. Co-immunoprecipitation, Myc-tagged deletion mutants, siRNA knockdown of B23, fluorescence microscopy for nuclear localization, flow cytometry for cell cycle Journal of Biological Chemistry Medium 15644315
2006 GADD45A physically associates with Aurora-A protein kinase and strongly inhibits Aurora-A kinase activity; this interaction antagonizes Aurora-A-induced centrosome amplification; Gadd45a-/- MEFs exhibit centrosome amplification that is restored by re-introduction of GADD45A. Co-immunoprecipitation, kinase activity assay, gadd45a-/- MEFs, re-introduction of exogenous GADD45A, centrosome counting Journal of Biological Chemistry High 16772293
2006 GADD45A protects hematopoietic cells from UV-induced apoptosis via a p38-NF-κB-mediated survival pathway, distinct from GADD45B's JNK inhibition pathway; Gadd45a-deficient bone marrow cells are sensitized to UVC- and VP-16-induced apoptosis and display defective G2/M arrest. Gadd45a-/- and Gadd45b-/- mouse models, bone marrow cell culture, flow cytometry for apoptosis and cell cycle, caspase-3 assay, pathway inhibitors, reconstitution by re-introduction of gadd45 genes Journal of Biological Chemistry Medium 16636063
2007 GADD45A overexpression promotes active DNA demethylation of methylation-silenced reporter plasmids; GADD45A knockdown leads to DNA hypermethylation; GADD45A is recruited to oct4 demethylation sites in Xenopus oocytes; GADD45A interacts with and requires the DNA repair endonuclease XPG for demethylation. Reporter plasmid demethylation assay, GADD45A knockdown (siRNA), Xenopus oocyte injection, co-immunoprecipitation with XPG, bisulfite sequencing Nature High 17268471
2007 GADD45A acts as an adapter to enhance interaction between β-catenin and Caveolin-1, promoting β-catenin translocation to the cell membrane and maintaining cell-cell adhesion/contact inhibition; GADD45A also facilitates UV-induced degradation of cytoplasmic and nuclear β-catenin in a p53-dependent manner via p38 kinase. Co-immunoprecipitation, inducible expression of GADD45A, subcellular fractionation, Western blot for β-catenin localization, p38 inhibitor Oncogene Medium 17452974
2007 GADD45A promotes base excision repair (BER); Gadd45a-null MEFs show delayed BER after MMS treatment and delayed removal of AP sites by APE1/Ref1; in Gadd45a-deficient cells, APE1 is mislocalized to cytoplasm and shows reduced interaction with PCNA. BER assay in Gadd45a-/- MEFs and Gadd45a-deficient human colon cancer cells, APE1 localization by immunostaining, co-immunoprecipitation of APE1 with PCNA Oncogene Medium 17599061
2008 In zebrafish embryos, GADD45A (Gadd45) promotes active DNA demethylation by acting as a non-enzymatic facilitator of coupled AID (5-meC deaminase) and Mbd4 (thymine glycosylase) activity; Gadd45 depletion attenuates demethylation of injected methylated DNA, and Gadd45 enhances functional interactions between AID/Mbd4. Zebrafish embryo injection, morpholino knockdown of Gadd45, methylated DNA injection assay, bisulfite sequencing, functional demethylation assay Cell High 19109892
2011 GADD45A binds RNA (but not single-stranded, double-stranded, or methylated DNA) in vitro; GADD45A is present in RNase-sensitive high-molecular-weight particles; GADD45A colocalizes with RNA helicase p68 and RNA-binding protein SC35 in nuclear speckles in an RNase-sensitive manner; G39 mutation impairs RNA binding, nuclear speckle localization, and DNA demethylation activity. RNA-binding assay in vitro, sucrose density gradient centrifugation, immunofluorescence colocalization, RNase treatment, point mutation (G39A and K45A) PLoS ONE Medium 21249130
2012 ATF4 transcription factor drives GADD45A expression in skeletal muscle under stress; GADD45A is necessary and sufficient for skeletal muscle atrophy induced by fasting, immobilization, or denervation; GADD45A acts as a myonuclear protein that represses anabolic genes (PGC-1α, Akt), reduces protein synthesis, and activates autophagy and caspase-mediated proteolysis. ATF4 muscle-specific knockout mice, GADD45A forced expression in muscle/myotubes, siRNA knockdown, multiple atrophy induction models (fasting, immobilization, denervation), gene expression profiling Journal of Biological Chemistry High 22692209
2013 GADD45A physically associates with mTOR kinase and suppresses mTOR-mediated STAT3 Ser-727 phosphorylation by dissociating the mTOR-STAT3 complex, thereby reducing VEGF expression and inhibiting tumor angiogenesis. Co-immunoprecipitation (GADD45A with mTOR and STAT3), phospho-STAT3 Western blot, VEGF ELISA, chorioallantoic membrane angiogenesis assay, Gadd45a-/- and overexpression systems Journal of Biological Chemistry Medium 23329839
2013 Ing1 tumor suppressor recruits GADD45A to H3K4me3-marked chromatin; reduced H3K4 methylation impairs GADD45A/Ing1 recruitment and gene-specific DNA demethylation, indicating that histone methylation directs GADD45A-mediated demethylation. ChIP, co-immunoprecipitation, H3K4 methylation manipulation, reporter demethylation assay Genes & Development Medium 23388825
2014 The lncRNA TARID interacts with both the TCF21 promoter and GADD45A; GADD45A in turn recruits thymine-DNA glycosylase (TDG) for base excision repair-mediated demethylation involving TET-catalyzed oxidation of 5mC; this defines a lncRNA–GADD45A–TDG axis for locus-specific demethylation. RNA immunoprecipitation, ChIP, co-immunoprecipitation of GADD45A with TDG, bisulfite sequencing, functional reporter demethylation assay Molecular Cell High 25087872
2015 GADD45A promotes TET-initiated oxidative DNA demethylation through physical interaction with TDG, enhancing TDG-mediated excision of 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC); double knockout of Gadd45a and Gadd45b in mouse ES cells causes hypermethylation of loci that are also TDG targets with 5fC enrichment. Co-immunoprecipitation (GADD45A-TDG), reporter demethylation assay with catalytically active TDG and TET, 5fC/5caC measurement in GADD45a/b double-KO ES cells, bisulfite sequencing Nucleic Acids Research High 25845601
2015 GADD45A physically interacts with TET1 and functionally cooperates with it; GADD45A requires endogenous TET1 for reporter demethylation and TET1 requires GADD45A; GADD45A promotes TET1-mediated mC oxidation and enhances 5fC/5caC removal. Co-immunoprecipitation (GADD45A-TET1), reporter demethylation assay, 5hmC/5fC/5caC quantification, siRNA knockdown epistasis Differentiation Medium 26546041
2015 GADD45A directly interacts with BECN1 (Beclin-1) via amino acids 71–81 and dissociates the BECN1-PIK3C3 complex, thereby inhibiting autophagosome initiation and suppressing autophagy. Co-immunoprecipitation, GST affinity isolation assay, LC3-II Western blot, autophagosome counting, bafilomycin A1 assay, BECN1 knockdown epistasis, GADD45A deletion mutants Autophagy Medium 26636486
2016 GADD45A forms a complex with MEKK4 (MAP3K4) in skeletal muscle fibers and increases MEKK4 kinase activity; MEKK4 activation is both sufficient to induce skeletal muscle fiber atrophy and required for GADD45A-mediated atrophy. Biochemical isolation of skeletal muscle proteins associating with GADD45A in vivo, co-immunoprecipitation, MEKK4 kinase assay, in vivo overexpression and knockdown in mouse skeletal muscle fibers Journal of Biological Chemistry High 27358404
2016 GADD45A expression in hematopoietic stem cells does not cause cell cycle arrest or apoptosis but strongly induces and accelerates differentiation; this differentiation induction is transmitted via p38 MAPK signaling. Retroviral GADD45A expression in murine HSCs, single-cell time-lapse microscopy, flow cytometry, in vivo transplantation, p38 MAPK pathway analysis Stem Cells Medium 26731607
2016 GADD45A acts as a chromatin relaxer; residue G39 is essential for interacting with core histones, opening chromatin, and enhancing somatic cell reprogramming; GADD45A destabilizes histone-DNA interactions and facilitates binding of Yamanaka factors to target loci. FRAP (fluorescence recovery after photobleaching), co-immunoprecipitation with histones, reprogramming efficiency assay, G39 point mutation, ChIP for Yamanaka factor binding EMBO Reports Medium 27702986
2019 GADD45A binds directly to R-loops (DNA-RNA hybrids) at CpG island promoters and mediates local DNA demethylation by recruiting TET1; GADD45A binding to R-loops at the TCF21 promoter (formed by lncRNA TARID) triggers demethylation and TCF21 expression; thousands of R-loop-dependent TET1 binding sites at CpG islands are identified. DRIP-seq (R-loop mapping), GADD45A ChIP-seq, TET1 ChIP-seq in ESCs, in vitro R-loop binding assay, RNase H1 depletion, bisulfite sequencing, co-immunoprecipitation Nature Genetics High 30617255
2006 Both basal transcription and ionizing radiation-enhanced transcription of GADD45A require an AP-1 element in the third intron; JunD binds the third intron AP-1 site as shown by EMSA and ChIP. Promoter/intron deletion reporter assays, EMSA, ChIP with JunD antibody Biochimica et Biophysica Acta Medium 17084916

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1992 A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia. Cell 3172 1423616
1994 Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen. Science (New York, N.Y.) 940 7973727
2002 DNA repair pathway stimulated by the forkhead transcription factor FOXO3a through the Gadd45 protein. Science (New York, N.Y.) 712 11964479
2007 Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethylation. Nature 595 17268471
1999 GADD45 induction of a G2/M cell cycle checkpoint. Proceedings of the National Academy of Sciences of the United States of America 555 10097101
2008 DNA demethylation in zebrafish involves the coupling of a deaminase, a glycosylase, and gadd45. Cell 525 19109892
1999 Induction of GADD45 and JNK/SAPK-dependent apoptosis following inducible expression of BRCA1. Cell 502 10367887
1999 Genomic instability in Gadd45a-deficient mice. Nature genetics 448 10508513
2013 Gadd45 in stress signaling, cell cycle control, and apoptosis. Advances in experimental medicine and biology 300 24104470
2012 GADD45 proteins: central players in tumorigenesis. Current molecular medicine 268 22515981
1995 Gadd45 is a nuclear cell cycle regulated protein which interacts with p21Cip1. Oncogene 241 7478594
1999 Gadd45, a p53-responsive stress protein, modifies DNA accessibility on damaged chromatin. Molecular and cellular biology 238 10022855
2014 Long noncoding RNA TARID directs demethylation and activation of the tumor suppressor TCF21 via GADD45A. Molecular cell 235 25087872
2019 GADD45A binds R-loops and recruits TET1 to CpG island promoters. Nature genetics 225 30617255
2008 Gadd45 in stress signaling. Journal of molecular signaling 208 18789159
1993 Analysis of the mammalian gadd45 gene and its response to DNA damage. The Journal of biological chemistry 203 8226988
2012 Active DNA demethylation by Gadd45 and DNA repair. Trends in cell biology 193 22341196
2012 Stress-induced skeletal muscle Gadd45a expression reprograms myonuclei and causes muscle atrophy. The Journal of biological chemistry 184 22692209
2005 Gadd45a, a p53- and BRCA1-regulated stress protein, in cellular response to DNA damage. Mutation research 180 15603758
2000 Role of Gadd45 in apoptosis. Biochemical pharmacology 171 10605933
2000 The GADD45 inhibition of Cdc2 kinase correlates with GADD45-mediated growth suppression. The Journal of biological chemistry 169 10747892
1992 Gadd45 and Gadd153 messenger RNA levels are increased during hypoxia and after exposure of cells to agents which elevate the levels of the glucose-regulated proteins. Cancer research 165 1617653
2009 DNA excision repair proteins and Gadd45 as molecular players for active DNA demethylation. Cell cycle (Georgetown, Tex.) 138 19377292
1997 Myc represses the growth arrest gene gadd45. Oncogene 138 9190899
2001 BRCA1 and GADD45 mediated G2/M cell cycle arrest in response to antimicrotubule agents. Oncogene 129 11593420
2011 Gadd45 proteins: relevance to aging, longevity and age-related pathologies. Ageing research reviews 126 21986581
2002 Genomic instability, centrosome amplification, cell cycle checkpoints and Gadd45a. Oncogene 124 12214253
2006 Gadd45a and Gadd45b protect hematopoietic cells from UV-induced apoptosis via distinct signaling pathways, including p38 activation and JNK inhibition. The Journal of biological chemistry 121 16636063
1995 Direct interaction of Gadd45 with PCNA and evidence for competitive interaction of Gadd45 and p21Waf1/Cip1 with PCNA. Oncogene 116 7478510
2011 Gadd45 stress sensors in malignancy and leukemia. Critical reviews in oncogenesis 115 22150313
2002 BRCA1 regulates GADD45 through its interactions with the OCT-1 and CAAT motifs. The Journal of biological chemistry 114 11777930
2000 Characterization of MyD118, Gadd45, and proliferating cell nuclear antigen (PCNA) interacting domains. PCNA impedes MyD118 AND Gadd45-mediated negative growth control. The Journal of biological chemistry 113 10828065
2000 Troglitazone induces apoptosis via the p53 and Gadd45 pathway in vascular smooth muscle cells. European journal of pharmacology 101 11068018
2005 Hematopoietic cells from Gadd45a- and Gadd45b-deficient mice are sensitized to genotoxic-stress-induced apoptosis. Oncogene 100 16170381
2005 Gadd45a expression induces Bim dissociation from the cytoskeleton and translocation to mitochondria. Molecular and cellular biology 95 15899854
2003 Gadd45a contributes to p53 stabilization in response to DNA damage. Oncogene 85 14627995
2007 Gadd45 in the response of hematopoietic cells to genotoxic stress. Blood cells, molecules & diseases 84 17659913
2002 GADD45 regulates G2/M arrest, DNA repair, and cell death in keratinocytes following ultraviolet exposure. The Journal of investigative dermatology 83 12164919
2003 CR6-interacting factor 1 interacts with Gadd45 family proteins and modulates the cell cycle. The Journal of biological chemistry 80 12716909
2015 Gadd45a promotes DNA demethylation through TDG. Nucleic acids research 76 25845601
2013 Gadd45a suppresses tumor angiogenesis via inhibition of the mTOR/STAT3 protein pathway. The Journal of biological chemistry 73 23329839
2009 Gadd45 modulation of intrinsic and extrinsic stress responses in myeloid cells. Journal of cellular physiology 72 18780287
2001 Oligomerization of human Gadd45a protein. The Journal of biological chemistry 70 11498536
1999 Glutamine deprivation induces the expression of GADD45 and GADD153 primarily by mRNA stabilization. The Journal of biological chemistry 67 10497233
2003 PPARgamma ligands inhibit cholangiocarcinoma cell growth through p53-dependent GADD45 and p21 pathway. Hepatology (Baltimore, Md.) 65 12829999
2022 GADD45 in Stress Signaling, Cell Cycle Control, and Apoptosis. Advances in experimental medicine and biology 63 35505159
2009 Gadd45 proteins as critical signal transducers linking NF-kappaB to MAPK cascades. Current cancer drug targets 61 20025601
2008 Gadd45-alpha and Gadd45-gamma utilize p38 and JNK signaling pathways to induce cell cycle G2/M arrest in Hep-G2 hepatoma cells. Molecular biology reports 61 19048389
2007 Base excision DNA repair defect in Gadd45a-deficient cells. Oncogene 60 17599061
2010 Estrogen receptor β causes a G2 cell cycle arrest by inhibiting CDK1 activity through the regulation of cyclin B1, GADD45A, and BTG2. Breast cancer research and treatment 58 21120602
2013 Gadd45 proteins: key players of repair-mediated DNA demethylation. Advances in experimental medicine and biology 57 24104472
2006 Gadd45a interacts with aurora-A and inhibits its kinase activity. The Journal of biological chemistry 55 16772293
2011 Gadd45a sensitizes medulloblastoma cells to irradiation and suppresses MMP-9-mediated EMT. Neuro-oncology 54 21813510
2024 GADD45A: With or without you. Medicinal research reviews 53 38264852
2018 GADD45A and CDKN1A are involved in apoptosis and cell cycle modulatory effects of viscumTT with further inactivation of the STAT3 pathway. Scientific reports 53 29636527
2005 B23 regulates GADD45a nuclear translocation and contributes to GADD45a-induced cell cycle G2-M arrest. The Journal of biological chemistry 53 15644315
1999 gadd45 is not required for activation of c-Jun N-terminal kinase or p38 during acute stress. The Journal of biological chemistry 51 10514426
2016 DNA-damage response gene GADD45A induces differentiation in hematopoietic stem cells without inhibiting cell cycle or survival. Stem cells (Dayton, Ohio) 50 26731607
2013 The role of the Gadd45 family in the nervous system: a focus on neurodevelopment, neuronal injury, and cognitive neuroepigenetics. Advances in experimental medicine and biology 47 24104475
2012 Fucoxanthin induces GADD45A expression and G1 arrest with SAPK/JNK activation in LNCap human prostate cancer cells. Anticancer research 47 22399598
2011 Gadd45a is an RNA binding protein and is localized in nuclear speckles. PloS one 45 21249130
2020 Interplay between BRCA1 and GADD45A and Its Potential for Nucleotide Excision Repair in Breast Cancer Pathogenesis. International journal of molecular sciences 43 32013256
2005 Gadd45 beta and Gadd45 gamma are critical for regulating autoimmunity. The Journal of experimental medicine 43 16287712
2013 Ing1 functions in DNA demethylation by directing Gadd45a to H3K4me3. Genes & development 42 23388825
2016 Gadd45a Protein Promotes Skeletal Muscle Atrophy by Forming a Complex with the Protein Kinase MEKK4. The Journal of biological chemistry 41 27358404
2015 GADD45a physically and functionally interacts with TET1. Differentiation; research in biological diversity 41 26546041
2013 Methylation-mediated repression of GADD45A and GADD45G expression in gastric cardia adenocarcinoma. International journal of cancer 41 23616123
2018 Down-regulation of GADD45A enhances chemosensitivity in melanoma. Scientific reports 38 29515153
2011 Gadd45a, Gadd45b and Gadd45g expression during mouse embryonic development. Gene expression patterns : GEP 37 21843656
2022 Role of GADD45A in myocardial ischemia/reperfusion through mediation of the JNK/p38 MAPK and STAT3/VEGF pathways. International journal of molecular medicine 36 36331027
2017 Retinoic acid inhibits white adipogenesis by disrupting GADD45A-mediated Zfp423 DNA demethylation. Journal of molecular cell biology 36 28992291
2004 Genetic interactions between Brca1 and Gadd45a in centrosome duplication, genetic stability, and neural tube closure. The Journal of biological chemistry 33 15123655
2014 GADD45 proteins: roles in cellular senescence and tumor development. Experimental biology and medicine (Maywood, N.J.) 32 24872428
2013 Gadd45 in modulation of solid tumors and leukemia. Advances in experimental medicine and biology 30 24104471
2013 Gadd45a regulates hematopoietic stem cell stress responses in mice. Blood 30 24371210
2020 Knockdown of GINS2 inhibits proliferation and promotes apoptosis through the p53/GADD45A pathway in non-small-cell lung cancer. Bioscience reports 29 32181475
2019 GADD45 promotes locus-specific DNA demethylation and 2C cycling in embryonic stem cells. Genes & development 29 31171699
2019 GADD45a Mediated Cell Cycle Inhibition Is Regulated By P53 In Bladder Cancer. OncoTargets and therapy 29 31571910
2006 Down-regulation of Gadd45 expression is associated with tumor differentiation in non-small cell lung cancer. Anticancer research 29 16827157
2005 GADD45-alpha expression in cirrhosis and hepatocellular carcinoma: relationship with DNA repair and proliferation. Human pathology 28 16260267
2017 GADD45A plays a protective role against temozolomide treatment in glioblastoma cells. Scientific reports 27 28821714
2016 Gadd45a is a heterochromatin relaxer that enhances iPS cell generation. EMBO reports 27 27702986
2011 GADD45A protects against cell death in dorsal root ganglion neurons following peripheral nerve injury. Journal of neuroscience research 27 21337369
2011 Gadd45a and Gadd45g regulate neural development and exit from pluripotency in Xenopus. Mechanisms of development 27 21854844
2013 Gadd45 proteins in immunity. Advances in experimental medicine and biology 26 24104473
2023 Embryonic Exposure to UV-328 Impairs the Cell Cycle in Zebrafish (Danio rerio) by Inhibiting the p38 MAPK/p53/Gadd45a Signaling Pathway. Environmental science & technology 25 37384941
2018 Gadd45a knockdown alleviates oxidative stress through suppressing the p38 MAPK signaling pathway in the pathogenesis of preeclampsia. Placenta 25 29908638
2017 GADD45a Regulates Olaquindox-Induced DNA Damage and S-Phase Arrest in Human Hepatoma G2 Cells via JNK/p38 Pathways. Molecules (Basel, Switzerland) 25 28098804
2016 New role and molecular mechanism of Gadd45a in hepatic fibrosis. World journal of gastroenterology 25 26973416
2015 GADD45A inhibits autophagy by regulating the interaction between BECN1 and PIK3C3. Autophagy 25 26636486
2007 Gadd45a activation protects melanoma cells from ultraviolet B-induced apoptosis. The Journal of investigative dermatology 25 17703175
2022 Gadd45 in DNA Demethylation and DNA Repair. Advances in experimental medicine and biology 24 35505162
2007 Gadd45a regulates beta-catenin distribution and maintains cell-cell adhesion/contact. Oncogene 24 17452974
2022 Gadd45 in Senescence. Advances in experimental medicine and biology 23 35505166
2007 Role of gadd45 in myeloid cells in response to hematopoietic stress. Blood cells, molecules & diseases 23 17686638
2024 Loss of the stress sensor GADD45A promotes stem cell activity and ferroptosis resistance in LGR4/HOXA9-dependent AML. Blood 22 38579286
2012 The GADD45a-GFP GreenScreen HC assay. Methods in molecular biology (Clifton, N.J.) 22 22147576
2005 The GADD45, ZBRK1 and BRCA1 pathway: quantitative analysis of mRNA expression in colon carcinomas. The Journal of pathology 22 15772983
2012 Gadd45a inhibits cell migration and invasion by altering the global RNA expression. Cancer biology & therapy 21 22825327
2006 Both the basal transcriptional activity of the GADD45A gene and its enhancement after ionizing irradiation are mediated by AP-1 element. Biochimica et biophysica acta 21 17084916

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