REV3L

Summary

REV3L (REV3 like, DNA directed polymerase zeta catalytic subunit, HGNC:9968) is a protein-coding gene on chromosome 6q21, encoding DNA polymerase zeta catalytic subunit (O60673). Catalytic subunit of the DNA polymerase zeta complex, an error-prone polymerase specialized in translesion DNA synthesis (TLS). It is a selective cancer dependency (DepMap: 54.6% of cell lines).

The protein encoded by this gene represents the catalytic subunit of DNA polymerase zeta, which functions in translesion DNA synthesis. The encoded protein can be found in mitochondria, where it protects DNA from damage. Defects in this gene are a cause of Mobius syndrome.

Source: NCBI Gene 5980 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Mobius syndrome (Strong, GenCC)
• GWAS associations: 15
• Clinical variants (ClinVar): 467 total — 3 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 42
• Cancer dependency (DepMap): dependent in 54.6% of screened cell lines
• MANE Select transcript: NM_001372078

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9968
Approved symbol	REV3L
Name	REV3 like, DNA directed polymerase zeta catalytic subunit
Location	6q21
Locus type	gene with protein product
Status	Approved
Aliases	POLZ, REV3
Ensembl gene	ENSG00000009413
Ensembl biotype	protein_coding
OMIM	602776
Entrez	5980

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 5 retained_intron, 3 protein_coding, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000358835, ENST00000368802, ENST00000413831, ENST00000422377, ENST00000434009, ENST00000435970, ENST00000460981, ENST00000462119, ENST00000467500, ENST00000470871, ENST00000492520, ENST00000494858

RefSeq mRNA: 4 — MANE Select: NM_001372078 NM_001286431, NM_001286432, NM_001372078, NM_002912

CCDS: CCDS5091, CCDS69177

Canonical transcript exons

ENST00000368802 — 32 exons

Exon	Start	End
ENSE00002700906	111482750	111483218
ENSE00003459929	111299033	111300156
ENSE00003475760	111309853	111310099
ENSE00003479686	111333123	111333367
ENSE00003486536	111367115	111368028
ENSE00003490768	111392876	111392972
ENSE00003519039	111349218	111349336
ENSE00003519781	111389106	111389210
ENSE00003534267	111357014	111357125
ENSE00003551089	111358822	111359014
ENSE00003560124	111307361	111307570
ENSE00003563797	111390086	111390180
ENSE00003567815	111343925	111344043
ENSE00003572779	111331676	111331784
ENSE00003573541	111387765	111387913
ENSE00003581132	111335469	111335610
ENSE00003592061	111351676	111351791
ENSE00003595719	111416283	111416472
ENSE00003598378	111381325	111381444
ENSE00003604471	111377701	111377843
ENSE00003616608	111379982	111380219
ENSE00003618044	111411480	111411554
ENSE00003631097	111405470	111405630
ENSE00003638224	111329532	111329738
ENSE00003641850	111313352	111313489
ENSE00003647860	111363853	111363978
ENSE00003651461	111388001	111388085
ENSE00003657795	111322569	111322678
ENSE00003667198	111372596	111376757
ENSE00003674458	111311069	111311259
ENSE00003680397	111315267	111315381
ENSE00003683322	111365265	111365344

Expression profiles

Bgee: expression breadth ubiquitous, 289 present calls, max score 97.17.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 28.8714 / max 508.2049, expressed in 1813 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
75089	12.3985	1672
75090	6.5645	1594
75093	2.5680	1073
75092	2.3265	1184
75095	1.5732	887
75088	1.0388	622
75096	0.9167	514
75094	0.7624	435
75086	0.3184	173
75091	0.2788	114

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	97.17	gold quality
skin of hip	UBERON:0001554	97.15	gold quality
endometrium	UBERON:0001295	95.52	gold quality
body of uterus	UBERON:0009853	95.28	gold quality
myometrium	UBERON:0001296	95.23	gold quality
synovial joint	UBERON:0002217	94.50	gold quality
uterus	UBERON:0000995	94.29	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	94.26	gold quality
endocervix	UBERON:0000458	94.21	gold quality
cauda epididymis	UBERON:0004360	93.62	gold quality
decidua	UBERON:0002450	93.35	gold quality
upper leg skin	UBERON:0004262	93.35	gold quality
cerebellar cortex	UBERON:0002129	93.04	gold quality
cerebellar hemisphere	UBERON:0002245	93.02	gold quality
cartilage tissue	UBERON:0002418	92.93	gold quality
seminal vesicle	UBERON:0000998	92.69	gold quality
caput epididymis	UBERON:0004358	92.63	gold quality
cerebellum	UBERON:0002037	92.55	gold quality
pericardium	UBERON:0002407	92.50	gold quality
right hemisphere of cerebellum	UBERON:0014890	92.49	gold quality
cerebellar vermis	UBERON:0004720	92.47	gold quality
ectocervix	UBERON:0012249	92.12	gold quality
ventricular zone	UBERON:0003053	91.98	gold quality
corpus epididymis	UBERON:0004359	91.90	gold quality
cortical plate	UBERON:0005343	91.85	gold quality
subcutaneous adipose tissue	UBERON:0002190	91.71	gold quality
pigmented layer of retina	UBERON:0001782	91.57	gold quality
endothelial cell	CL:0000115	91.42	gold quality
colonic epithelium	UBERON:0000397	91.42	gold quality
urethra	UBERON:0000057	91.21	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-MTAB-10287	yes	101.62
E-MTAB-8142	yes	93.31
E-HCAD-35	yes	51.48
E-ANND-3	yes	17.24
E-GEOD-93593	yes	4.63
E-MTAB-6379	no	208.54

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): STAT1, TP53

miRNA regulators (miRDB)

155 targeting REV3L, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-25-3P	99.98	74.60	1817
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4789-5P	99.98	70.76	2721

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 54.6% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• plays a critical role in the induction of mutations (PMID:12459444)
• REV3 gene plays a role not only in lesion-targeted DNA mutagenesis, but also in mutagenesis on undamaged DNA templates that is called untargeted mutation. (PMID:12717825)
• downregulation of rev3 might have occurred early during tumorigenesis. (PMID:18622427)
• The study revealed that suppression of REV3 delayed spontaneous S phase progression and suppression of REV3 limits spontaneous and DNA damage induced mutagenesis. (PMID:18779149)
• REV3L Overexpression confers chemoresistance to cisplatin in gliomas. (PMID:19289490)
• DNA polymerase zeta cooperates with polymerases kappa and iota in translesion DNA synthesis across pyrimidine photodimers in cells from xeroderma pigmentosum variant patients. (PMID:19564618)
• REV1 and Polzeta facilitate repair of interstrand cross-links independently of PCNA monoubiquitination and Poleta, whereas RAD18 plus Poleta, REV1, and Polzeta are all necessary for replicative bypass of cisplatin intrastrand DNA cross-links. (PMID:20028736)
• To clarify the structural basis of the interaction between REV7 and REV3, REV7 was crystallized in complex with a REV3 fragment. (PMID:20054135)
• function of REV7 as an adapter protein to recruit Polzeta to a DNA lesion site (PMID:20164194)
• show the first crystal structure of REV7 in complex with a fragment of REV3 polymerase (residues 1847-1898) and reveal the mechanism underlying REV7-REV3 interaction (PMID:20164194)
• Data suggest that REV3 plays an important role in different cellular growth periods and physiological conditions. (PMID:20466635)
• our data suggest a significant role of genetic variation in the polymerase zeta subunit genes regarding the development and progression of BC. (PMID:21455670)
• The REV1/Polzeta complex maintains genomic stability by directly participating in DNA double-stranded break repair. (PMID:21926160)
• Findings indicate that depletion of REV3 not only can amend cisplatin-based cancer therapy but also can be applied for susceptible cancers as a potential monotherapy. (PMID:22028621)
• REV7 subunit of pol zeta mediated the interaction between REV3 and the REV1 C terminus. (PMID:22303021)
• REV3L rs465646 variant modifies lung cancer susceptibility in Chinese Han population by affecting miRNA-mediated gene regulation (PMID:22349819)
• DNA polymerase zeta transgene participates directly in immunoglobulin hypermutation. (PMID:22547703)
• analysis of the crystal structure of the ternary complex composed of the C-terminal domain of human REV1, REV7, and a REV3 fragment (PMID:22859296)
• ternary complex of the C-terminal domain of human REV1 in complex with REV7 bound to a REV3 fragment has been crystallized. The crystals belonged to space group P3(1)21, with unit-cell parameters a = b = 74.7, c = 124.5 A (PMID:22869133)
• A long-term depletion of Rev3 in cultured human cells results in massive genomic instability and severe cell cycle arrest. (PMID:23303771)
• DNA polymerase zeta is a predictor of poor prognosis for cervical cancer patients who are resistant to chemoradiation. (PMID:23456618)
• Human Pol eta inserts a nucleotide opposite the lesion, followed by Pol zeta extending the DNA primer; thus, the two complement each other to fully bypass the cisplatin cross-link. (PMID:24449906)
• Our results suggest for the first time that REV1 and REV3L SNPs might serve as potential predictive markers of outcome of cisplatin-based chemotherapy (PMID:24956248)
• Single nucleotide polymorphisms in RBPJ, IL1R1, REV3L, TRAF3IP2, IRF1 and ICOS showed association with rheumatoid arthritis in black South Africans. (PMID:25014791)
• Rev3, the catalytic subunit of polymerase zeta (Pol zeta), is involved in DNA replication under conditions of replication stress caused by deoxyribonucleotide shortage and/or imbalance in human lung adenocarcinoma cells. (PMID:25113059)
• data suggest that REV3L plays an important role in regulating cervical cancer cellular response to cisplatin (PMID:25781640)
• finding that PLXND1 and REV3L mutations are responsible for a proportion of MBS patients suggests that de novo mutations in other genes might account for other MBS patients (PMID:26068067)
• Taken together, we demonstrated that inhibition of REV3L sensitized lung cancer H1299 cells to cisplatin treatment (PMID:26165320)
• REV3 functions in mammalian mitochondria and that mitochondrial REV3 is associated with the tumorigenic potential of cells. (PMID:26462070)
• REV3L plays an important role in esophageal squamous cell carcinoma (ESCC) progression and chemoresistance, and is a potential diagnostic marker and therapeutic target for ESCC (PMID:26752104)
• loss-of-function of REV3L dramatically enhanced the sensitivity of SCCHN cells to dacomitinib by the loss of both translesion synthesis and homologous recombination pathways. (PMID:26790612)
• The data directly show that, in the human genome, DNA Pol-eta and Rev1 bypass cyclobutane pyrimidine dimers and 6-4PP at replication forks, while only 6-4PP are also tolerated by a Rev3L-dependent gap-filling mechanism, independent of S phase. (PMID:27095204)
• The results indicate that human DNA polymerase zeta plays important roles in induction of mutations, clastogenicity and in cellular survival of the damaged human cells. (PMID:27338670)
• Following challenge with AFB1, survival of mouse cells deficient in pol zeta (Rev3L(-/-)) was significantly reduced relative to Rev3L(+/-) cells or Rev3L(-/-) cells complemented through expression of the wild-type human REV3L (PMID:27849610)
• REV3/ATR knockdown enhances the cytotoxicity of cisplatin in non-small cell lung cells. (PMID:28075014)
• We have identified and characterised a novel DNA damage response mechanism in melanoma. Instead of increasing levels of RAD51 on encountering cisplatin-induced interstrand crosslinks during replication, melanoma cells shut down RAD51 synthesis and instead boost levels of translesion synthesis DNA polymerase zeta to allow replication to proceed (PMID:29254481)
• These results demonstrate a previously unrecognized relationship between p53 and REV3L in cancer cell metabolism and may lead to improvements in chemotherapy treatment plans that reduce cisplatin resistance in lung cancer. (PMID:29307819)
• These data provide a model whereby interbase H-bonding interactions at the DNA terminus promote lesion bypass and extension by human DNA polymerase zeta. (PMID:30222325)
• Results suggest a pivotal role of miR29a in mediating NSCLC cell sensitivity towards cisplatin through the regulation of REV3L. (PMID:30535450)
• miR-145 was downregulated in esophageal squamous cell carcinoma (ESCC) tumor tissues and cells, while REV3L was upregulated in ESCC tumor tissues. Overexpression of miR-145 decreased REV3L mRNA and protein level in ESCC cell line KYSE150, while decreased miR-145 increased REV3L mRNA and protein level in esophageal epithelium cell line (HEEC). (PMID:31072625)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	rev3l	ENSDARG00000058801
mus_musculus	Rev3l	ENSMUSG00000019841
rattus_norvegicus	Rev3l	ENSRNOG00000000593

Paralogs (3): NEXMIF (ENSG00000050030), POLD1 (ENSG00000062822), POLA1 (ENSG00000101868)

Protein

Protein identifiers

DNA polymerase zeta catalytic subunit — O60673 (reviewed: O60673)

Alternative names: Protein reversionless 3-like

All UniProt accessions (3): O60673, F2Z3A1, H0Y5T4

UniProt curated annotations — full annotation on UniProt →

Function. Catalytic subunit of the DNA polymerase zeta complex, an error-prone polymerase specialized in translesion DNA synthesis (TLS). Lacks an intrinsic 3’-5’ exonuclease activity and thus has no proofreading function.

Subunit / interactions. Heterodimer with MAD2L2. This dimer forms the minimal DNA polymerase zeta complex (Pol-zeta2), with REV3L bearing DNA polymerase catalytic activity, although its activity is very low in this context. Component of the tetrameric Pol-zeta complex (Pol-zeta4), which consists of REV3L, MAD2L2, POLD2 and POLD3; Pol-zeta4 is the fully active form of DNA polymerase zeta. Forms a quaternary complex with POLK, MAD2L2 and REV1, where REV3L-bound MAD2L2 and POLK are able to bind simultaneously to REV1 forming the stable translesion synthesis (TLS) machinery therefore bridging the inserter and extender polymerases.

Subcellular location. Nucleus.

Tissue specificity. Ubiquitously expressed.

Cofactor. Binds 1 [4Fe-4S] cluster.

Domain organisation. Its C-terminal part could serve as the catalytic domain during nucleotide polymerization, while its N-terminal part could provide sites for protein-protein interactions with other factors during translesion DNA synthesis. The CysB motif binds 1 4Fe-4S cluster and is required for the formation of polymerase complexes.

Similarity. Belongs to the DNA polymerase type-B family.

Isoforms (2)

UniProt ID	Names	Canonical?
O60673-1	1	yes
O60673-2	2

RefSeq proteins (4): NP_001273360, NP_001273361, NP_001359007, NP_002903 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006133	DNA-dir_DNA_pol_B_exonuc	Domain
IPR006134	DNA-dir_DNA_pol_B_multi_dom	Domain
IPR006172	DNA-dir_DNA_pol_B	Family
IPR012337	RNaseH-like_sf	Homologous_superfamily
IPR017964	DNA-dir_DNA_pol_B_CS	Conserved_site
IPR023211	DNA_pol_palm_dom_sf	Homologous_superfamily
IPR025687	Znf-C4pol	Domain
IPR030559	PolZ_Rev3	Family
IPR032757	DUF4683	Domain
IPR036397	RNaseH_sf	Homologous_superfamily
IPR042087	DNA_pol_B_thumb	Homologous_superfamily
IPR043502	DNA/RNA_pol_sf	Homologous_superfamily
IPR056435	DPOD/Z_N	Domain
IPR056447	REV3_N	Domain

Pfam: PF00136, PF03104, PF14260, PF15735, PF24055, PF24065

Catalyzed reactions (Rhea), 1 shown:

• DNA(n) + a 2’-deoxyribonucleoside 5’-triphosphate = DNA(n+1) + diphosphate (RHEA:22508)

UniProt features (82 total): sequence variant 27, compositionally biased region 17, region of interest 15, binding site 8, modified residue 4, mutagenesis site 2, strand 2, helix 2, chain 1, zinc finger region 1, short sequence motif 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

14 structures.

PDB	Method	Resolution (Å)
6BCD	X-RAY DIFFRACTION	1.43
6BC8	X-RAY DIFFRACTION	1.68
5O8K	X-RAY DIFFRACTION	1.8
3ABD	X-RAY DIFFRACTION	1.9
4EXT	X-RAY DIFFRACTION	1.9
6WS0	X-RAY DIFFRACTION	2.24
6KEA	X-RAY DIFFRACTION	2.35
6WS5	X-RAY DIFFRACTION	2.47
3ABE	X-RAY DIFFRACTION	2.6
4GK0	X-RAY DIFFRACTION	2.7
6EKM	X-RAY DIFFRACTION	2.76
3VU7	X-RAY DIFFRACTION	2.8
6BI7	X-RAY DIFFRACTION	2.8
4GK5	X-RAY DIFFRACTION	3.21

Predicted structure (AlphaFold)

No AlphaFold model available for O60673 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (8): 3042; 3045; 3054; 3057; 3086; 3089; 3099; 3104

Post-translational modifications (4): 1030, 1041, 1724, 1967

Mutagenesis-validated functional residues (2):

Position	Phenotype
2614	loss of dna polymerase catalytic activity; when associated with n-2783.
2783	loss of dna polymerase catalytic activity; when associated with n-2614.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-110312	Translesion synthesis by REV1
R-HSA-5655862	Translesion synthesis by POLK
R-HSA-5656121	Translesion synthesis by POLI

MSigDB gene sets: 408 (showing top): GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_DN, TGGTGCT_MIR29A_MIR29B_MIR29C, MORF_MSH3, MODULE_255, SP3_Q3, MORF_BRCA1, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, MORF_ATRX, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, MODULE_317, JOHANSSON_GLIOMAGENESIS_BY_PDGFB_UP, AREB6_01, GOBP_DNA_DAMAGE_TOLERANCE, KAUFFMANN_DNA_REPAIR_GENES, GGGCATT_MIR365

GO Biological Process (9): double-strand break repair via homologous recombination (GO:0000724), DNA synthesis involved in DNA repair (GO:0000731), DNA-templated DNA replication (GO:0006261), translesion synthesis (GO:0019985), error-prone translesion synthesis (GO:0042276), DNA biosynthetic process (GO:0071897), DNA replication (GO:0006260), DNA repair (GO:0006281), DNA damage response (GO:0006974)

GO Molecular Function (12): nucleotide binding (GO:0000166), DNA binding (GO:0003677), DNA-directed DNA polymerase activity (GO:0003887), zinc ion binding (GO:0008270), 4 iron, 4 sulfur cluster binding (GO:0051539), nucleic acid binding (GO:0003676), protein binding (GO:0005515), transferase activity (GO:0016740), nucleotidyltransferase activity (GO:0016779), DNA polymerase activity (GO:0034061), metal ion binding (GO:0046872), iron-sulfur cluster binding (GO:0051536)

GO Cellular Component (6): nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), zeta DNA polymerase complex (GO:0016035), site of DNA damage (GO:0090734), nuclear lumen (GO:0031981)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Translesion synthesis by Y family DNA polymerases bypasses lesions on DNA template	3

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA biosynthetic process	3
DNA metabolic process	3
binding	2
nuclear lumen	2
cellular anatomical structure	2
recombinational repair	1
double-strand break repair	1
DNA repair	1
DNA replication	1
DNA damage tolerance	1
DNA synthesis involved in DNA replication	1
translesion synthesis	1
nucleic acid biosynthetic process	1
DNA damage response	1
cellular response to stress	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
nucleic acid binding	1
DNA polymerase activity	1
transition metal ion binding	1
iron-sulfur cluster binding	1
catalytic activity	1
transferase activity, transferring phosphorus-containing groups	1
nucleotidyltransferase activity	1
catalytic activity, acting on DNA	1
cation binding	1
metal cluster binding	1
intracellular membrane-bounded organelle	1
intracellular membraneless organelle	1
DNA polymerase complex	1
chromosome	1
nucleus	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

2146 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
REV3L	MAD2L2	Q9UI95	999
REV3L	REV1	Q9UBZ9	999
REV3L	POLD2	P49005	995
REV3L	POLD3	Q15054	974
REV3L	POLH	Q9Y253	919
REV3L	POLL	Q9UGP5	879
REV3L	RAD18	Q9NS91	846
REV3L	POLE	Q07864	839
REV3L	POLM	Q9NP87	805
REV3L	UBE2V2	Q15819	771
REV3L	RAD52	P43351	759
REV3L	MSH6	P52701	731
REV3L	POLK	Q9UBT6	717
REV3L	SHLD2	Q86V20	716
REV3L	FANCD2	Q9BXW9	711

IntAct

38 interactions, top by confidence:

A	B	Type	Score
MAD2L2	REV3L	psi-mi:“MI:0915”(physical association)	0.640
MAD2L2	REV3L	psi-mi:“MI:0407”(direct interaction)	0.640
POLD2	REV3L	psi-mi:“MI:0914”(association)	0.530
ERBB2	HAX1	psi-mi:“MI:0914”(association)	0.530
REV3L	H1-1	psi-mi:“MI:0915”(physical association)	0.400
REV3L	H1-2	psi-mi:“MI:0915”(physical association)	0.400
REV3L	H3-3A	psi-mi:“MI:0915”(physical association)	0.400
REV3L	H1-5	psi-mi:“MI:0915”(physical association)	0.400
REV3L	SLTM	psi-mi:“MI:0915”(physical association)	0.400
MEF2A	REV3L	psi-mi:“MI:0914”(association)	0.350
POLD2	P4HA2	psi-mi:“MI:0914”(association)	0.350
KLHL22	TRAV18	psi-mi:“MI:0914”(association)	0.350
POLD3	ESYT2	psi-mi:“MI:0914”(association)	0.350
	TTC8	psi-mi:“MI:0914”(association)	0.350
ATF2	PLOD2	psi-mi:“MI:0914”(association)	0.350
ATF3	ILVBL	psi-mi:“MI:0914”(association)	0.350
CASP3	TMEM223	psi-mi:“MI:0914”(association)	0.350
CTNNA1	ILVBL	psi-mi:“MI:0914”(association)	0.350
FOS	ILVBL	psi-mi:“MI:0914”(association)	0.350
GATA2	ILVBL	psi-mi:“MI:0914”(association)	0.350
STAT3	IDH3B	psi-mi:“MI:0914”(association)	0.350
ATF3	TMEM223	psi-mi:“MI:0914”(association)	0.350
CEBPA	ESYT2	psi-mi:“MI:0914”(association)	0.350
FOS	TMEM223	psi-mi:“MI:0914”(association)	0.350

BioGRID (92): RPL14 (Co-fractionation), GPR27 (Synthetic Growth Defect), RRM1 (Synthetic Growth Defect), CFLAR (Synthetic Growth Defect), LMTK3 (Synthetic Growth Defect), CCR6 (Synthetic Growth Defect), CACNA1A (Synthetic Growth Defect), COPZ1 (Synthetic Growth Defect), CDY1 (Synthetic Growth Defect), CSAD (Synthetic Growth Defect), A1BG (Synthetic Growth Defect), TXN (Synthetic Growth Defect), SLC16A10 (Synthetic Growth Defect), ATAD1 (Synthetic Growth Defect), RFXAP (Synthetic Growth Defect)

ESM2 similar proteins: A0A087WRU1, A0JNH1, A2RUB1, A6QNQ6, B0S6S9, B1WC58, D3Z987, D3ZJ47, E1BC15, O60673, P28358, P28359, P56716, P70347, Q0P5X5, Q0VAV2, Q0VBV7, Q15468, Q2M2Z5, Q3UXL4, Q3V089, Q49A88, Q569L8, Q5BQN8, Q5CZC0, Q5QGS0, Q5T1N1, Q5VWN6, Q60988, Q61493, Q62924, Q6ZP01, Q6ZU52, Q6ZVD7, Q80U59, Q80WQ8, Q86WS4, Q86YC2, Q8CB14, Q8IUR6

Diamond homologs: D3ZGX1, O60673, Q5DTT1, Q5QGS0, Q61493, F4I1N8, O48901, O54747, O59610, P03198, P15436, P28339, P28340, P28857, P30315, P30316, P30320, P30321, P46588, P52431, P54358, P90829, P97283, Q1HVC1, Q2HRD0, Q3KSP1, Q51334, Q54N97, Q58295, Q69025, Q9DKT8, Q9GSR1, Q9HH06, Q9LRE6, Q9LVN7, Q9QJ32, P14284, Q5TGY3, Q6PAL7, Q766Z3

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 33 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Signaling by Interleukins	6	13.8×	6e-04
Cytokine Signaling in Immune system	6	8.7×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
response to ethanol	5	24.4×	4e-04
positive regulation of gene expression	7	9.0×	9e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

467 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	1
Uncertain significance	281
Likely benign	76
Benign	46

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
1072419	NM_001372078.1(REV3L):c.6220_6221del (p.Gln2074fs)	Pathogenic
3246165	NC_000006.11:g.(?111640856)(111644166_?)del	Pathogenic
4723246	NM_001372078.1(REV3L):c.8842C>T (p.Arg2948Ter)	Pathogenic
221624	NM_001372078.1(REV3L):c.559A>T (p.Arg187Trp)	Likely pathogenic

SpliceAI

6024 predictions. Top by Δscore:

Variant	Effect	Δscore
6:111310095:TTTTC:T	acceptor_gain	1.0000
6:111310100:C:CC	acceptor_gain	1.0000
6:111310111:C:CT	acceptor_gain	1.0000
6:111310112:A:T	acceptor_gain	1.0000
6:111311261:T:C	acceptor_gain	1.0000
6:111313346:CCTTA:C	donor_loss	1.0000
6:111313347:CTTAC:C	donor_loss	1.0000
6:111313348:TTA:T	donor_loss	1.0000
6:111313349:TACC:T	donor_loss	1.0000
6:111313350:A:T	donor_loss	1.0000
6:111313466:T:C	acceptor_gain	1.0000
6:111313466:T:TC	acceptor_gain	1.0000
6:111313485:TATAC:T	acceptor_gain	1.0000
6:111313487:TAC:T	acceptor_gain	1.0000
6:111313490:C:T	acceptor_loss	1.0000
6:111313491:T:G	acceptor_loss	1.0000
6:111315261:TCTTA:T	donor_loss	1.0000
6:111315262:CTTAC:C	donor_loss	1.0000
6:111315263:TTACC:T	donor_loss	1.0000
6:111315264:TAC:T	donor_loss	1.0000
6:111315265:ACCTT:A	donor_loss	1.0000
6:111315266:C:CG	donor_loss	1.0000
6:111315377:ACATA:A	acceptor_gain	1.0000
6:111315378:CATA:C	acceptor_gain	1.0000
6:111315378:CATAC:C	acceptor_gain	1.0000
6:111315379:ATA:A	acceptor_gain	1.0000
6:111315380:TA:T	acceptor_gain	1.0000
6:111315381:ACTA:A	acceptor_loss	1.0000
6:111315382:C:A	acceptor_loss	1.0000
6:111315382:C:CC	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000040072 (6:111473644 C>G,T), RS1000045951 (6:111427834 G>A), RS1000049609 (6:111409553 T>C), RS1000056808 (6:111425027 A>G), RS1000087778 (6:111342540 C>G,T), RS1000097048 (6:111421627 A>T), RS1000102675 (6:111299174 C>T), RS1000107048 (6:111317716 G>A), RS1000109604 (6:111409412 G>A), RS1000109923 (6:111329120 T>C), RS1000117504 (6:111440050 C>A,T), RS1000134203 (6:111336375 T>C), RS1000148750 (6:111349800 GA>G,GAA), RS1000165905 (6:111370342 T>C), RS1000187605 (6:111480030 C>A)

Disease associations

OMIM: gene MIM:602776 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
Mobius syndrome	Strong	Autosomal dominant

Mondo (2): colon carcinoma (MONDO:0002032), Mobius syndrome (MONDO:0008006)

Orphanet (0):

HPO phenotypes

42 total (30 of 42 shown, HPO-id order):

HPO	Term
HP:0000044	Hypogonadotropic hypogonadism
HP:0000175	Cleft palate
HP:0000194	Open mouth
HP:0000218	High palate
HP:0000232	Everted lower lip vermilion
HP:0000286	Epicanthus
HP:0000298	Mask-like facies
HP:0000347	Micrognathia
HP:0000365	Hearing impairment
HP:0000486	Strabismus
HP:0000498	Blepharitis
HP:0000505	Visual impairment
HP:0000508	Ptosis
HP:0000602	Ophthalmoplegia
HP:0000691	Microdontia
HP:0000717	Autism
HP:0001156	Brachydactyly
HP:0001252	Hypotonia
HP:0001270	Motor delay
HP:0001522	Death in infancy
HP:0001608	Abnormality of the voice
HP:0001762	Talipes equinovarus
HP:0002015	Dysphagia
HP:0002804	Arthrogryposis multiplex congenita
HP:0003202	Skeletal muscle atrophy
HP:0004050	Absent hand
HP:0004209	Clinodactyly of the 5th finger
HP:0004408	Abnormality of the sense of smell
HP:0005914	Aplasia/Hypoplasia involving the metacarpal bones
HP:0006101	Finger syndactyly

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST001725_23	Inflammatory bowel disease	1.000000e-13
GCST002738_16	Psoriasis	8.000000e-12
GCST002740_48	Inflammatory skin disease	6.000000e-18
GCST004131_98	Inflammatory bowel disease	4.000000e-10
GCST004133_60	Ulcerative colitis	6.000000e-10
GCST005312_23	Menopause (age at onset)	3.000000e-08
GCST007323_68	Risk-taking tendency (4-domain principal component model)	1.000000e-11
GCST007327_204	Smoking status (ever vs never smokers)	4.000000e-23
GCST008810_79	Smoking initiation (ever regular vs never regular)	2.000000e-17
GCST009240_221	Serum metabolite levels (CMS)	5.000000e-13
GCST009242_456	Serum metabolite levels	6.000000e-09
GCST010002_332	Refractive error	3.000000e-10
GCST010242_390	HDL cholesterol levels	5.000000e-10
GCST010244_186	Triglyceride levels	2.000000e-08
GCST011703_78	Smoking initiation	4.000000e-18

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004704	age at menopause
EFO:0008579	risk-taking behaviour
EFO:0004318	smoking behavior
EFO:0005670	smoking initiation
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004530	triglyceride measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D020331	Mobius Syndrome	C07.465.299.825; C10.292.319.825; C10.292.562.700.375.750; C11.590.436.400.750; C16.131.077.578; C16.614.595

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs3218592	Efficacy	3	capecitabine;fluorouracil	Metastatic neoplasm
rs462779	Efficacy	3	cisplatin	Osteosarcoma

PharmGKB variants

5 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs462779	REV3L	3	2.25	1	cisplatin
rs465646	REV3L		0.00	0
rs3204953	REV3L		0.00	0
rs3218592	REV3L	3	0.00	1	capecitabine;fluorouracil
rs240993	REV3L		0.00	0

CTD chemical–gene interactions

55 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
methylmercuric chloride	increases expression	3
bisphenol A	increases expression, affects cotreatment	3
sodium arsenite	decreases expression, affects cotreatment, increases abundance	2
mercuric bromide	increases expression, affects cotreatment	2
Dexamethasone	affects cotreatment, increases expression	2
Formaldehyde	increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tretinoin	decreases expression, increases expression	2
Valproic Acid	increases methylation, increases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
triphenyl phosphate	affects expression	1
trichostatin A	increases expression	1
arsenite	decreases reaction, affects binding	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
potassium chromate(VI)	decreases expression, affects cotreatment	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
tamibarotene	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	increases expression, affects cotreatment	1
jinfukang	decreases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Vehicle Emissions	increases abundance, increases expression	1

Cellosaurus cell lines

10 cell lines: 10 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_1R12	HCT116-REV3L(+/-)	Cancer cell line	Male
CVCL_JG98	POLZ Y2779F-POLK+/-	Cancer cell line	Male
CVCL_JG99	POLZ Y2779F-POLH+/-	Cancer cell line	Male
CVCL_JH04	POLZ L2618F	Cancer cell line	Male
CVCL_JH06	POLZ Y2779F	Cancer cell line	Male
CVCL_JH08	POLZ CD MSH-	Cancer cell line	Male
CVCL_JH09	POLZ D2781N	Cancer cell line	Male
CVCL_M248	POLZ KO	Cancer cell line	Male
CVCL_M249	POLZ KO MSH-	Cancer cell line	Male
CVCL_M250	POLZ L2618M	Cancer cell line	Male

Clinical trials (associated diseases)

301 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01169220	PHASE4	COMPLETED	Bowel Preparation for Inpatient Colonoscopy
NCT01170754	PHASE4	COMPLETED	Miralax (PEG 3350) vs. Golytely as Bowel Preparation for Screening Colonoscopy
NCT02052557	PHASE4	COMPLETED	The Effect of Exparel on Post Operative Pain and Narcotic Use After Colon Surgery
NCT02078726	PHASE4	COMPLETED	Glucagon Use in Colonoscopies
NCT02231203	PHASE4	COMPLETED	Effect of Omega-3 Fatty Acids on the Perioperative Immune Response and Erythrocyte Function
NCT02314871	PHASE4	COMPLETED	Effects of Different Types of Perioperative Analgesia on Minimal Residual Disease Development After Colon Cancer Surgery
NCT02746432	PHASE4	UNKNOWN	Insulin Therapy Reduce Post-Operative Inflammatory Response After Curative Colorectal Cancer Resection: Randomization Controlled Trial
NCT02887365	PHASE4	UNKNOWN	A Phase II Study of Tegafur-Uracil as Maintenance Chemotherapy in Patients With Stage II of Colon Cancer
NCT02937506	PHASE4	COMPLETED	Patient Satisfaction With Propofol for Out Patient Colonoscopy
NCT02958566	PHASE4	UNKNOWN	Multimodal Narcotic Limited Perioperative Pain Control With Colorectal Surgery
NCT04269369	PHASE4	UNKNOWN	Implementation of Pre-emptive Geno- and Phenotyping in 5-Fluorouracil- or Capecitabine-treated Patients
NCT04311099	PHASE4	COMPLETED	Optimal Peripheral Nerve Block After Minimally Invasive Colon Surgery
NCT04709770	PHASE4	UNKNOWN	Low-volume vs High-volume Polyethylene Glycol Based Bowel Preparation for Colonoscopy in People Receiving Hemodialysis
NCT05250648	PHASE4	RECRUITING	Clinical Trial on HIPEC With Mitomycin C in Colon Cancer Peritoneal Metastases (GECOP-MMC)
NCT00002968	PHASE3	COMPLETED	Edrecolomab in Treating Patients With Stage II Colon Cancer
NCT00003835	PHASE3	COMPLETED	Combination Chemotherapy in Treating Patients With Stage III Colon Cancer
NCT00003873	PHASE3	COMPLETED	Fluorouracil With or Without Eniluracil in Treating Patients With Advanced Colorectal Cancer
NCT00004931	PHASE3	COMPLETED	Fluorouracil Plus Leucovorin With or Without Oxaliplatin in Treating Patients With Stage II or Stage III Colon Cancer
NCT00005036	PHASE3	COMPLETED	Irinotecan Compared With Combination Chemotherapy in Treating Patients With Advanced Colorectal Cancer
NCT00005094	PHASE3	COMPLETED	Celecoxib to Prevent Colorectal Cancer in Patients Who Have Undergone Surgery to Remove Polyps
NCT00025337	PHASE3	COMPLETED	Combination Chemotherapy With or Without Bevacizumab Compared With Bevacizumab Alone in Treating Patients With Advanced or Metastatic Colorectal Cancer That Has Been Previously Treated
NCT00070122	PHASE3	TERMINATED	Combination Chemotherapy and Bevacizumab in Treating Patients With Locally Advanced, Metastatic, or Recurrent Colorectal Cancer
NCT00079274	PHASE3	COMPLETED	Comparison of Combination Chemotherapy Regimens With or Without Cetuximab in Treating Patients Who Have Undergone Surgery For Stage III Colon Cancer
NCT00096278	PHASE3	COMPLETED	Fluorouracil, Leucovorin, and Oxaliplatin With or Without Bevacizumab in Treating Patients Who Have Undergone Surgery for Stage II or Stage III Colon Cancer
NCT00188305	PHASE3	COMPLETED	A Randomized Trial of Cancer Risk and Health Education in Relatives of Colorectal Cancer Patients
NCT00195585	PHASE3	COMPLETED	Study Evaluating Isovorin in Colon Cancer
NCT00217737	PHASE3	ACTIVE_NOT_RECRUITING	Oxaliplatin, Leucovorin, and Fluorouracil With or Without Bevacizumab in Treating Patients Who Have Undergone Surgery for Stage II Colon Cancer
NCT00230646	PHASE3	COMPLETED	Promoting Physical Activity After Colorectal Cancer
NCT00309530	PHASE3	COMPLETED	Randomized Study on Adjuvant Chemotherapy and Adjuvant Chemo-Immunotherapy in Colon Carcinoma Dukes C
NCT00309543	PHASE3	COMPLETED	Randomized Trial on Adjuvant Chemotherapy in Colon Carcinoma Dukes B
NCT00337389	PHASE3	UNKNOWN	Phase III Randomized Study of 5-FU, CoFactor, and Avastin vs. 5-FU, LV and Avastin for First-Line Colorectal Cancer.
NCT00467922	PHASE3	COMPLETED	An Assessment of Goal-Directed Intraoperative Fluid Management in Hand Assisted Laparoscopic Colectomy
NCT00499369	PHASE3	TERMINATED	Irinotecan and Cetuximab With or Without Bevacizumab in Treating Patients With Metastatic Colorectal Cancer That Progressed During First-Line Therapy
NCT00509444	PHASE3	COMPLETED	Cancer Prevention and Treatment Among African American Older Adults: Treatment Trial
NCT00646607	PHASE3	COMPLETED	FOLFOX-4 3months Versus 6 Months and Bevacizumab as Adjuvant Therapy for Patients With Stage II/III Colon Cancer
NCT00687830	PHASE3	COMPLETED	Efficacy of Morning-only Bowel Preparation for Afternoon Colonoscopy.
NCT00756548	PHASE3	COMPLETED	BLI850-302: BLI850 vs an Approved Active Control Bowel Preparation in Adult Subjects Undergoing Colonoscopy
NCT00756977	PHASE3	COMPLETED	BLI850 vs an Active Control Bowel Preparation in Adult Subjects Undergoing Colonoscopy
NCT00894725	PHASE3	COMPLETED	Laparoscopic Versus Open Left Colonic Resection
NCT00911170	PHASE3	COMPLETED	PAVES: Pegfilgrastim Anti-vascular Endothelial Growth Factor (VEGF) Evaluation Study