Details for: RFWD3

Gene ID: 55159

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: RFWD3

Ensembl ID: ENSG00000168411

Description: ring finger and WD repeat domain 3

Cell Significance Landscape

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • erythroblast CL0000765
    CSI 4.83
    rCSI 12.82%
    PRS 94.63
  • pro-B cell CL0000826
    CSI 4.01
    rCSI 3.32%
    PRS 95.31
  • common myeloid progenitor CL0000049
    CSI 3.11
    rCSI 2.51%
    PRS 95.47
  • retinal bipolar neuron CL0000748
    CSI 2.81
    rCSI 5.25%
    PRS 89.04
  • cerebral cortex endothelial cell CL1001602
    CSI 2.79
    rCSI 4.83%
    PRS 91.56
  • renal beta-intercalated cell CL0002201
    CSI 2.7
    rCSI 6.44%
    PRS 95.03
  • granulocyte monocyte progenitor cell CL0000557
    CSI 2.64
    rCSI 2.28%
    PRS 95.76
  • kidney interstitial alternatively activated macrophage CL1000695
    CSI 2.62
    rCSI 6.82%
    PRS 96.03
  • choroid plexus epithelial cell CL0000706
    CSI 2.58
    rCSI 4.22%
    PRS 90
  • hepatic stellate cell CL0000632
    CSI 2.58
    rCSI 9.65%
    PRS 92.29
  • lung secretory cell CL1000272
    CSI 2.48
    rCSI 6.14%
    PRS 95.95
  • neuroblast (sensu Nematoda and Protostomia) CL0000338
    CSI 2.33
    rCSI 2.69%
    PRS 88.89
  • extravillous trophoblast CL0008036
    CSI 2.25
    rCSI 2.79%
    PRS 93.25
  • kidney connecting tubule epithelial cell CL1000768
    CSI 2.24
    rCSI 5.67%
    PRS 91.17
  • megakaryocyte-erythroid progenitor cell CL0000050
    CSI 2.1
    rCSI 1.89%
    PRS 93.95
  • dendritic cell, human CL0001056
    CSI 2.05
    rCSI 3.15%
    PRS 97.87
  • ependymal cell CL0000065
    CSI 1.88
    rCSI 3.81%
    PRS 80.99
  • placental villous trophoblast CL2000060
    CSI 1.74
    rCSI 2.7%
    PRS 93.25
  • innate lymphoid cell CL0001065
    CSI 1.65
    rCSI 3.4%
    PRS 89.02
  • basal cell of epidermis CL0002187
    CSI 1.6
    rCSI 2.84%
    PRS 70.43
  • lymphoid lineage restricted progenitor cell CL0000838
    CSI 1.42
    rCSI 5.53%
    PRS 99.04
  • parietal epithelial cell CL1000452
    CSI 1.27
    rCSI 3.4%
    PRS 91.49
  • helper T cell CL0000912
    CSI 1.24
    rCSI 1.76%
    PRS 89.95
  • promonocyte CL0000559
    CSI 1.16
    rCSI 2%
    PRS 95.56
  • melanocyte of skin CL1000458
    CSI 1.11
    rCSI 1.51%
    PRS 70.38
  • blood vessel smooth muscle cell CL0019018
    CSI 0.43
    rCSI 3.49%
    PRS 93.72

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

Comma-separated if multiple.
Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [RFWD3](/details-gene/55159) (ring finger and WD repeat domain 3) is a protein-coding gene located on chromosome 16q23.1 that encodes a crucial E3 ubiquitin ligase. This enzyme plays a central role in the DNA damage response (DDR), particularly in the repair of double-strand breaks and interstrand cross-links. Research has established its function in protein ubiquitination, which facilitates the proper coordination of DNA repair factors at sites of damage ([Link](https://doi.org/10.1016/j.molcel.2017.04.021), [Link](https://doi.org/10.1016/j.molcel.2017.04.022)). Its significance is underscored by the finding that biallelic mutations in [RFWD3](/details-gene/55159) cause Fanconi anemia, a severe inherited bone marrow failure syndrome characterized by genomic instability ([Link](https://doi.org/10.1172/jci92069)). **Overall**, expression data shows [RFWD3](/details-gene/55159) is most significant in highly proliferative hematopoietic progenitor cells, such as the [erythroblast](/details-cell/CL0000765) and [pro-B cell](/details-cell/CL0000826), consistent with a critical role in maintaining genomic integrity during rapid cell division. ## Cellular Roles and Expression Landscape The expression profile of [RFWD3](/details-gene/55159) highlights its importance in cells undergoing active proliferation and differentiation, as well as in certain specialized, terminally differentiated cell types. The highest significance scores are observed in hematopoietic precursors, including [erythroblast](/details-cell/CL0000765), [pro-B cell](/details-cell/CL0000826), [common myeloid progenitor](/details-cell/CL0000049), and [megakaryocyte-erythroid progenitor cell](/details-cell/CL0000050). This pattern strongly suggests that [RFWD3](/details-gene/55159) is a key component of the machinery that safeguards the genome during the high replicative stress associated with hematopoiesis. Beyond the hematopoietic system, [RFWD3](/details-gene/55159) also shows significant expression in a diverse array of other cell types. These include neuronal cells like the [retinal bipolar neuron](/details-cell/CL0000748), endothelial cells such as the [cerebral cortex endothelial cell](/details-cell/CL1001602), and various specialized epithelial cells, including [renal beta-intercalated cell](/details-cell/CL0002201) and [choroid plexus epithelial cell](/details-cell/CL0000706). This broader expression pattern may indicate a more universal housekeeping role in managing DNA damage arising from metabolic activity or environmental insults, in addition to its function during DNA replication. ## Pathways and Molecular Function Functionally, [RFWD3](/details-gene/55159) is deeply integrated into the cellular response to genomic stress. Its primary molecular function is categorized as [ubiquitin protein ligase activity](/details-cell/GO:0061630), which is critical for its role in the [Dna damage response](/details-cell/GO:0006974). Specifically, it is involved in complex repair pathways, including [double-strand break repair via homologous recombination](/details-cell/GO:0000724) and [interstrand cross-link repair](/details-cell/GO:0036297). The protein localizes to the [nucleus](/details-cell/GO:0005634) and is recruited to the [site of dna damage](/details-cell/GO:0090734). Mechanistically, [RFWD3](/details-gene/55159) interacts with key DDR proteins. It has been shown to participate in a complex with Mdm2 to positively regulate p53 stability ([Link](https://doi.org/10.1073/pnas.0912094107)) and directly binds p53 ([p53 binding](/details-cell/GO:0002039)). A critical aspect of its function is its association with Replication Protein A (RPA) at stalled replication forks. RFWD3-mediated ubiquitination of RPA is essential for resolving these forks and for the timely removal of both RPA and RAD51 to allow for the completion of homologous recombination ([Link](https://doi.org/10.1016/j.molcel.2015.09.011), [Link](https://doi.org/10.1016/j.molcel.2017.04.022)). This regulatory role solidifies its status as a master coordinator of DNA repair protein dynamics. ## Research Directions The established role of [RFWD3](/details-gene/55159) in DNA repair, coupled with its expression profile, raises several testable hypotheses for future research. 1. **Hypothesis:** The significant expression of [RFWD3](/details-gene/55159) in non-proliferating but metabolically active cells, such as [retinal bipolar neuron](/details-cell/CL0000748)s and specialized kidney cells, suggests a function beyond the management of replication-associated stress. It may play a critical role in repairing DNA damage induced by high levels of oxidative stress, a common feature of these cell types. 2. **Hypothesis:** Given its crucial function in homologous recombination and interstrand cross-link repair, the expression level of [RFWD3](/details-gene/55159) in cancer cells may be a key determinant of their sensitivity to specific chemotherapies (e.g., platinum-based agents) and targeted therapies like PARP inhibitors. Reduced [RFWD3](/details-gene/55159) function could induce a state of synthetic lethality when combined with these agents. A compelling experimental approach to test the second hypothesis would be to use a CRISPR-Cas9 system to generate [RFWD3](/details-gene/55159) knockout and isogenic control cell lines from a cancer type known to rely on homologous recombination for survival (e.g., ovarian or breast cancer). These cell lines could then be treated with a dose-response matrix of a PARP inhibitor (e.g., olaparib) and an interstrand cross-linking agent (e.g., cisplatin). Cell viability assays and analysis of DNA damage markers (e.g., γH2AX foci) would determine if the loss of [RFWD3](/details-gene/55159) sensitizes cancer cells to these DNA-damaging treatments. From a therapeutic perspective, [RFWD3](/details-gene/55159) presents a complex profile. As an essential gene whose loss causes severe disease, systemic inhibition is likely to be highly toxic. However, its role as a facilitator of DNA repair makes it an attractive target for **inhibition** within the context of oncology. A small molecule inhibitor targeting the E3 ligase activity of [RFWD3](/details-gene/55159) could be developed as a chemo- or radio-sensitizing agent, potentially overcoming resistance mechanisms in tumors that rely on robust DNA repair pathways for survival.

Genular Protein ID: 952390783

Symbol: RFWD3_HUMAN

Name: RING finger and WD repeat domain-containing protein 3

UniProtKB Accession Codes:

Q6PCD5 A8K585 B2RE35 D3DUJ8 Q5XKR3 Q9H9Q3 Q9NVT4

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 1 CTD 1 ChiTaRS 1 DIP 1 DMDM 1 DNASU 1 DisGeNET 1 EC 1 EMBL 9 Ensembl 2 ExpressionAtlas 1 GO 17 Gene3D 2 GeneCards 1 GeneReviews 1 GeneTree 1 GenomeRNAi 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 6 KEGG 1 MANE-Select 1 MIM 3 MINT 1 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 1 OrthoDB 1 PANTHER 2 PDB 1 PDBsum 1 PRO 1 PROSITE 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 Pumba 1 RNAct 1 RefSeq 5 SIGNOR 1 SMART 2 SMR 1 STRING 1 SUPFAM 2 SignaLink 1 TreeFam 1 UCSC 1 UniPathway 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 15616553

Title: The sequence and analysis of duplication-rich human chromosome 16.

PubMed ID: 15616553

DOI: 10.1038/nature03187

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 18669648

Title: A quantitative atlas of mitotic phosphorylation.

PubMed ID: 18669648

DOI: 10.1073/pnas.0805139105

PubMed ID: 20173098

Title: RFWD3-Mdm2 ubiquitin ligase complex positively regulates p53 stability in response to DNA damage.

PubMed ID: 20173098

DOI: 10.1073/pnas.0912094107

PubMed ID: 21504906

Title: E3 ligase RFWD3 participates in replication checkpoint control.

PubMed ID: 21504906

DOI: 10.1074/jbc.m111.222869

PubMed ID: 21558276

Title: RING finger and WD repeat domain 3 (RFWD3) associates with replication protein A (RPA) and facilitates RPA-mediated DNA damage response.

PubMed ID: 21558276

DOI: 10.1074/jbc.m111.222802

PubMed ID: 23186163

Title: Toward a comprehensive characterization of a human cancer cell phosphoproteome.

PubMed ID: 23186163

DOI: 10.1021/pr300630k

PubMed ID: 26474068

Title: RFWD3-dependent ubiquitination of RPA regulates repair at stalled replication forks.

PubMed ID: 26474068

DOI: 10.1016/j.molcel.2015.09.011

PubMed ID: 28575657

Title: RPA-mediated recruitment of the E3 ligase RFWD3 is vital for interstrand crosslink repair and human health.

PubMed ID: 28575657

DOI: 10.1016/j.molcel.2017.04.021

PubMed ID: 28691929

Title: Biallelic mutations in the ubiquitin ligase RFWD3 cause Fanconi anemia.

PubMed ID: 28691929

DOI: 10.1172/jci92069

PubMed ID: 28575658

Title: RFWD3-mediated ubiquitination promotes timely removal of both RPA and RAD51 from dna damage sites to facilitate homologous recombination.

PubMed ID: 28575658

DOI: 10.1016/j.molcel.2017.04.022

PubMed ID: 33321094

Title: The ubiquitin ligase RFWD3 is required for translesion DNA synthesis.

PubMed ID: 33321094

DOI: 10.1016/j.molcel.2020.11.029

Sequence Information:

  • Length: 774
  • Mass: 85094
  • Checksum: EF6E0E186FD2E580
  • Sequence:
    • MAHEAMEYDV QVQLNHAEQQ PAPAGMASSQ GGPALLQPVP ADVVSSQGVP SILQPAPAEV 
ISSQATPPLL QPAPQLSVDL TEVEVLGEDT VENINPRTSE QHRQGSDGNH TIPASSLHSM 
TNFISGLQRL HGMLEFLRPS SSNHSVGPMR TRRRVSASRR ARAGGSQRTD SARLRAPLDA 
YFQVSRTQPD LPATTYDSET RNPVSEELQV SSSSDSDSDS SAEYGGVVDQ AEESGAVILE 
EQLAGVSAEQ EVTCIDGGKT LPKQPSPQKS EPLLPSASMD EEEGDTCTIC LEQWTNAGDH 
RLSALRCGHL FGYRCISTWL KGQVRKCPQC NKKARHSDIV VLYARTLRAL DTSEQERMKS 
SLLKEQMLRK QAELESAQCR LQLQVLTDKC TRLQRRVQDL QKLTSHQSQN LQQPRGSQAW 
VLSCSPSSQG QHKHKYHFQK TFTVSQAGNC RIMAYCDALS CLVISQPSPQ ASFLPGFGVK 
MLSTANMKSS QYIPMHGKQI RGLAFSSYLR GLLLSASLDN TIKLTSLETN TVVQTYNAGR 
PVWSCCWCLD EANYIYAGLA NGSILVYDVR NTSSHVQELV AQKARCPLVS LSYMPRAASA 
AFPYGGVLAG TLEDASFWEQ KMDFSHWPHV LPLEPGGCID FQTENSSRHC LVTYRPDKNH 
TTIRSVLMEM SYRLDDTGNP ICSCQPVHTF FGGPTCKLLT KNAIFQSPEN DGNILVCTGD 
EAANSALLWD AASGSLLQDL QTDQPVLDIC PFEVNRNSYL ATLTEKMVHI YKWE