NTHL1

Summary

NTHL1 (nth like DNA glycosylase 1, HGNC:8028) is a protein-coding gene on chromosome 16p13.3, encoding Endonuclease III-like protein 1 (P78549). Bifunctional DNA N-glycosylase with associated apurinic/apyrimidinic (AP) lyase function that catalyzes the first step in base excision repair (BER), the primary repair pathway for the repair of oxidative DNA damage.

The protein encoded by this gene is a DNA N-glycosylase of the endonuclease III family. Like a similar protein in E. coli, the encoded protein has DNA glycosylase activity on DNA substrates containing oxidized pyrimidine residues and has apurinic/apyrimidinic lyase activity.

Source: NCBI Gene 4913 — RefSeq curated summary.

At a glance

• Gene–disease (curated): NTHL1-deficiency tumor predisposition syndrome (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 1,808 total — 114 pathogenic, 33 likely-pathogenic
• Phenotypes (HPO): 18
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_002528

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8028
Approved symbol	NTHL1
Name	nth like DNA glycosylase 1
Location	16p13.3
Locus type	gene with protein product
Status	Approved
Aliases	NTH1, OCTS3
Ensembl gene	ENSG00000065057
Ensembl biotype	protein_coding
OMIM	602656
Entrez	4913

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 18 protein_coding, 5 retained_intron, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000219066, ENST00000561841, ENST00000561862, ENST00000562120, ENST00000562951, ENST00000565406, ENST00000566380, ENST00000567727, ENST00000568513, ENST00000623977, ENST00000651522, ENST00000651570, ENST00000651583, ENST00000903566, ENST00000903567, ENST00000903568, ENST00000903569, ENST00000925705, ENST00000925706, ENST00000925707, ENST00000925708, ENST00000925709, ENST00000925710, ENST00000925711, ENST00000925713, ENST00000971053

RefSeq mRNA: 3 — MANE Select: NM_002528 NM_001318193, NM_001318194, NM_002528

CCDS: CCDS10457

Canonical transcript exons

ENST00000651570 — 6 exons

Exon	Start	End
ENSE00000665105	2046128	2046366
ENSE00003493853	2044630	2044800
ENSE00003497108	2040133	2040238
ENSE00003556751	2039820	2040047
ENSE00003643331	2043567	2043726
ENSE00003842419	2047709	2047834

Expression profiles

Bgee: expression breadth ubiquitous, 211 present calls, max score 94.90.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.8585 / max 119.1715, expressed in 1713 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
155899	11.7821	1713
155898	0.0765	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	94.90	gold quality
apex of heart	UBERON:0002098	93.17	gold quality
mucosa of transverse colon	UBERON:0004991	92.55	gold quality
right uterine tube	UBERON:0001302	89.94	gold quality
putamen	UBERON:0001874	89.25	gold quality
right hemisphere of cerebellum	UBERON:0014890	89.01	gold quality
cerebellar hemisphere	UBERON:0002245	88.86	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.85	gold quality
cerebellar cortex	UBERON:0002129	88.62	gold quality
nucleus accumbens	UBERON:0001882	88.60	gold quality
caudate nucleus	UBERON:0001873	88.56	gold quality
right frontal lobe	UBERON:0002810	88.19	gold quality
right lung	UBERON:0002167	87.85	gold quality
Brodmann (1909) area 9	UBERON:0013540	87.46	gold quality
liver	UBERON:0002107	87.38	gold quality
tibial nerve	UBERON:0001323	86.98	gold quality
right ovary	UBERON:0002118	86.83	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	86.70	gold quality
ectocervix	UBERON:0012249	86.66	gold quality
oocyte	CL:0000023	86.52	gold quality
prefrontal cortex	UBERON:0000451	86.49	gold quality
cerebellum	UBERON:0002037	86.42	gold quality
transverse colon	UBERON:0001157	86.41	gold quality
spleen	UBERON:0002106	86.30	gold quality
endocervix	UBERON:0000458	86.19	gold quality
muscle layer of sigmoid colon	UBERON:0035805	86.19	gold quality
amygdala	UBERON:0001876	86.10	gold quality
cingulate cortex	UBERON:0003027	86.02	gold quality
right coronary artery	UBERON:0001625	85.86	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.78	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.78

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): BRCA1, ELF1, MYC, POU2F1

miRNA regulators (miRDB)

3 targeting NTHL1, 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-MIR-329-3P	99.91	66.56	1234
HSA-MIR-362-3P	99.91	66.38	1267
HSA-MIR-4272	98.76	68.74	1810

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 39)

• NTH1 is involved in removal of 8-oxoguanine from 8-oxoguanine/guanine mispairs in DNA (PMID:11328882)
• recombinant hNTH1 lacking 55, 72 or 80 residues from the N terminus had four- to fivefold higher activities than the full-length enzyme (PMID:12144783)
• substrate selectivity of mammalian NTH1 and the concomitant selective stimulation of activity by APE1 are indicative of selective repair of oxidative damage in different regions of the genome (PMID:12519758)
• dimerization of hNTH1 involving the N-terminal tail masks the inhibitory effect of this tail and plays a critical role in its catalytic turnover in the cell (PMID:14522981)
• hNTH1 and hNEIL1 but not hNEIL2 excised the two stereoisomers of thymine glycol (5R-Tg and 5S-Tg), but their isomer specificity was markedly different (PMID:14734554)
• search for the factors interacting with NTH1 shows GST-NTH1 fusion protein precipitates proliferating cell nuclear antigen (PCNA) and p53 as well as XPG from human cell-free extracts (PMID:15358233)
• NTH1 is a DNA glycosylase that excise 5-formyluracil, 5-hydroxymethyluracil and Thymine glycol in human cells. (PMID:15533839)
• hNTH1 plays two roles in the processing of radiation damages: repair of potentially lethal single lesions and generation of lethal double strand breaks at clustered damage sites. (PMID:16111924)
• Nth1 released 5R,6S 2’-deoxyribonucleoside diastereoisomer (Tg2) much more rapidly than cis 5S,6R-deoxyribonucleoside diastereoisomer (Tg1) regardless of the opposing purine. Neil1 released Thymine glycol non-stereoselectively. (PMID:16446124)
• The damage specificity of human homologues of Endo III (hNTHl) and Endo VIII (hNEIL1 and hNEIL2) is compared to elucidate the repair role in cells. (PMID:17150535)
• These observations suggest that access to sterically occluded lesions entails the partial, reversible unwrapping of DNA from the histone octamer, allowing hNTH1 to capture its DNA substrate when it is in an unwound state. (PMID:17923696)
• YB-1 binds specifically to the auto-inhibitory domain of hNTH1, providing a mechanism by which YB-1 stimulates hNTH1 activity. (PMID:18307537)
• Downregulation of NTH1 is associated with gastric cancer. (PMID:19414504)
• we demonstrated that hNEIL1 and hNTH1 cleave Oz sites as efficiently as 5-hydroxyuracil sites. Thus, hNEIL1 and hNTH1 can repair Oz lesions (PMID:22465744)
• A homozygous loss-of-function germline mutation in the NTHL1 gene predisposes to a new subtype of BER-associated adenomatous polyposis and colorectal cancer. (PMID:25938944)
• NTH1 polymorphisms may be associated with non-small cell lung cancer pathogenesis. (PMID:26400813)
• This study extends the description of biallelic mutations in NTHL1 beyond the single c.268C–>T,p.Q90* mutation that was observed previously. (PMID:26559593)
• We therefore found published evidence to support the association between variants in NTHL1 and RPS20 with CRC. (PMID:27713038)
• Both Ntg1 and its human homologue, NTHL1, can be SUMO-modified in response to oxidative stress. (PMID:27839712)
• WT NTHL1 (human) and Nth (E. coli) are remarkably alike with respect to specificity of glycosylase reaction, and although NTHL1 is a much slower enzyme than Nth, the tighter binding of NTHL1 compensates, resulting in similar kcat/Kd values for both enzymes with each of the substrates tested. For NTHL1 Gln287Ala, specificity for substrates positioned opposite G is lost, but not that of substrates positioned opposite A. (PMID:28292631)
• Data indicate that DNA glycosylases MYH, UNG2, MPG, NTH1, NEIL1, 2 and 3 on nascent DNA. (PMID:28575236)
• NTHL1 in these extracts was able to excise thymine glycol from both naked DNA and sites in nucleosomes that earlier studies had shown to be sterically accessible. However, the same extracts were able to excise lesions from sterically-occluded sites in nucleosomes only after the addition of Mg2+/ATP. (PMID:28709015)
• This paper demonstrates that cellular NTH1 protein is induced in response to oxidative stress following hydrogen peroxide treatment of cells and that accumulation of NTH1 on chromatin is exacerbated in the absence of TRIM26. (PMID:29610152)
• The processing of the lesions was evaluated by purified enzyme cocktails of hNTH1 and hOGG1 as well as with a HeLa cell extract. Interestingly, the yield of double-strand breaks (DSBs) resulting from the processing of the bistranded lesions are appreciably lower when the DNA is treated with the HeLa cell extract compared with the relevant purified enzyme cocktail in both models (PMID:30207305)
• The results suggest that the NTHL1 variants Q90X, Y130X, R153X, and Q287X, but not R19Q, V179I, V217F, or G286S, were defective in 5OHU repair and the alleles encoding them were considered to be pathogenic for NTHL1-associated polyposis. (PMID:30552997)
• he lyase activity of hNTHL1, and the 3’ diesterase activity of APE1, which had been seen as relatively dispensable, may have been preserved during evolution to enhance base excision repair (BER) in chromatin (PMID:30649547)
• NTHL1 is a multi-tumor predisposition gene with a high lifetime risk for extracolonic cancers and a typical mutational signature observed across tumor types, which can assist in the recognition of this syndrome. (PMID:30753826)
• NTHL1 biallelic mutations seldom cause colorectal cancer, serrated polyposis or a multi-tumor phenotype, in absence of colorectal adenomas. (PMID:31227763)
• An Excimer Clamp for Measuring Damaged-Base Excision by the DNA Repair Enzyme NTH1. (PMID:32109332)
• Monoallelic NTHL1 Loss-of-Function Variants and Risk of Polyposis and Colorectal Cancer. (PMID:32860789)
• Evaluating the role of NTHL1 p.Q90* allele in inherited breast cancer predisposition. (PMID:32949222)
• NTHL1 in genomic integrity, aging and cancer. (PMID:33087284)
• Further delineation of the NTHL1 associated syndrome: A report from the French Oncogenetic Consortium. (PMID:33454955)
• Prevalence and Characterization of Biallelic and Monoallelic NTHL1 and MSH3 Variant Carriers From a Pan-Cancer Patient Population. (PMID:34250384)
• Caught in motion: human NTHL1 undergoes interdomain rearrangement necessary for catalysis. (PMID:34871433)
• Human endonuclease III/NTH1: focusing on the [4Fe-4S] cluster and the N-terminal domain. (PMID:36279116)
• Concurrent Reduced Expression of Contiguous PKD1, TSC2 and NTHL1 Leading to Kidney Diseases and Multiple Diverse Renal Cancers. (PMID:36581342)
• NTHL1 is a recessive cancer susceptibility gene. (PMID:38036545)
• Enhanced Sampling for Conformational Changes and Molecular Mechanisms of Human NTHL1. (PMID:38483510)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	nthl1	ENSDARG00000042881
mus_musculus	Nthl1	ENSMUSG00000041429
rattus_norvegicus	Nthl1	ENSRNOG00000012213
drosophila_melanogaster	Nthl1	FBGN0032907
caenorhabditis_elegans		WBGENE00011201

Paralogs (1): MUTYH (ENSG00000132781)

Protein

Protein identifiers

Endonuclease III-like protein 1 — P78549 (reviewed: P78549)

Alternative names: Bifunctional DNA N-glycosylase/DNA-(apurinic or apyrimidinic site) lyase

All UniProt accessions (7): P78549, A0A494BZZ6, A0A494C106, E5KTI5, H3BPD5, H3BRL9, H3BUV2

UniProt curated annotations — full annotation on UniProt →

Function. Bifunctional DNA N-glycosylase with associated apurinic/apyrimidinic (AP) lyase function that catalyzes the first step in base excision repair (BER), the primary repair pathway for the repair of oxidative DNA damage. The DNA N-glycosylase activity releases the damaged DNA base from DNA by cleaving the N-glycosidic bond, leaving an AP site. The AP-lyase activity cleaves the phosphodiester bond 3’ to the AP site by a beta-elimination. Primarily recognizes and repairs oxidative base damage of pyrimidines. Also has 8-oxo-7,8-dihydroguanine (8-oxoG) DNA glycosylase activity. Acts preferentially on DNA damage opposite guanine residues in DNA. Is able to process lesions in nucleosomes without requiring or inducing nucleosome disruption.

Subunit / interactions. Interacts with YBX1. Interacts with ERCC5/XPG; the interaction stimulates NTHL1 activity and NTHL1 binding to its DNA substrate.

Subcellular location. Nucleus. Mitochondrion.

Tissue specificity. Widely expressed with highest levels in heart and lowest levels in lung and liver.

Post-translational modifications. Ubiquitinated by TRIM26; leading to proteasomal degradation.

Disease relevance. Familial adenomatous polyposis 3 (FAP3) [MIM:616415] A form of familial adenomatous polyposis, a condition characterized by the development of multiple colorectal adenomatous polyps, benign neoplasms derived from glandular epithelium. Some affected individuals may develop colorectal carcinoma. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. APE1 displaces NTHL1 from the N-glycosylase-generated AP site in DNA, thereby increasing the turnover of the DNA N-glycosylase activity. AP lyase activity is stimulated by YBX1. ERCC5/XPG stimulates NTHL1 activity and NTHL1 binding to its DNA substrate.

Cofactor. Binds 1 [4Fe-4S] cluster. The cluster does not appear to play a role in catalysis, but is probably involved in the proper positioning of the enzyme along the DNA strand.

Similarity. Belongs to the Nth/MutY family.

Isoforms (3)

UniProt ID	Names	Canonical?
P78549-2	2, M+1	yes
P78549-1	1, M-8
P78549-3	3, M+8

RefSeq proteins (3): NP_001305122, NP_001305123, NP_002519* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000445	HhH_motif	Conserved_site
IPR003265	HhH-GPD_domain	Domain
IPR003651	Endonuclease3_FeS-loop_motif	Conserved_site
IPR004036	Endonuclease-III-like_CS2	Conserved_site
IPR011257	DNA_glycosylase	Homologous_superfamily
IPR023170	HhH_base_excis_C	Homologous_superfamily
IPR030841	NTH1	Family

Pfam: PF00633, PF00730

Enzyme classification (BRENDA):

• EC 4.2.99.18 — DNA-(apurinic or apyrimidinic site) lyase (BRENDA: 46 organisms, 543 substrates, 374 inhibitors, 166 Km, 138 kcat entries)

Substrate kinetics (BRENDA)

68 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
5’-CTCTCCCTTC-5,6-DIHYDROURACIL-CTCCTTTCCTCT-3'	—	13
DNA CONTAINING AN ABASIC SITE	100–413	9
5’-GACAAGCGCAG-(5R,6S)-2’-DEOXY-5,6-DIHYDROXYURI	—	8
DNA CONTAINING 5-OH-C/A	—	6
5’-GACAAGCGCAG-(5S,6R)-2’-DEOXY-5,6-DIHYDROXYURI	—	5
DNA CONTAINING 5-OH-C/G	—	5
OLIGOMER WITH G/U PAIR	0.0001–0.0013	5
43-MER OLIGONUCLEOTIDE CONTAINING APURINIC/APYRI	—	4
5’-CTCTCCCTTC-8-OXO-7,8-DIHYDROGUANINE-CTCCTTTCC	0.0006–0.0013	4
AP-DNA	0.0001–0.011	4
DNA	0.0009–0.0017	4
DNA CONTAINING APURINIC/APYRIMIDINIC SITES	—	4
THF-CONTAINING OLIGONUCLEOTIDE	0.0001–0.0002	4
12-MER OLIGODEOXYRIBONUCLEOTIDE CONTAINING A NAT	0.0001–0.0002	2
18-MER CONTAINING P33-LABELED TETRAHYDROFURAN	—	2

Catalyzed reactions (Rhea), 1 shown:

• 2’-deoxyribonucleotide-(2’-deoxyribose 5’-phosphate)-2’-deoxyribonucleotide-DNA = a 3’-end 2’-deoxyribonucleotide-(2,3-dehydro-2,3-deoxyribose 5’-phosphate)-DNA + a 5’-end 5’-phospho-2’-deoxyribonucleoside-DNA + H(+) (RHEA:66592)

UniProt features (51 total): helix 16, mutagenesis site 6, sequence variant 5, binding site 4, sequence conflict 4, modified residue 2, splice variant 2, strand 2, compositionally biased region 2, transit peptide 1, chain 1, site 1, domain 1, region of interest 1, turn 1, short sequence motif 1, active site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
7RDT	X-RAY DIFFRACTION	2.1
7RDS	X-RAY DIFFRACTION	2.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P78549-F1	82.87	0.74

Functional residue map

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

Catalytic / active sites (2): 231 (important for catalytic activity); 212 (nucleophile; for n-glycosylase activity)

Ligand- & substrate-binding residues (4): 292; 298; 282; 289

Post-translational modifications (2): 63, 65

Mutagenesis-validated functional residues (6):

Position	Phenotype
32–34	sorted to the cytoplasm.
34	sorted to both nuclei and mitochondria.
34	sorted to the cytoplasm.
49	sorted to both nuclei and mitochondria.
212	inactivates enzyme.
212	85-fold reduction in activity. uncouples the glycosylase activity from the lyase activity. shows glycosylase activity wi

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-110328	Recognition and association of DNA glycosylase with site containing an affected pyrimidine
R-HSA-110329	Cleavage of the damaged pyrimidine
R-HSA-110357	Displacement of DNA glycosylase by APEX1
R-HSA-9630221	Defective NTHL1 substrate processing
R-HSA-9630222	Defective NTHL1 substrate binding

MSigDB gene sets: 225 (showing top): GOMF_ENDONUCLEASE_ACTIVITY, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOMF_NUCLEASE_ACTIVITY, ENK_UV_RESPONSE_KERATINOCYTE_UP, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, KAUFFMANN_DNA_REPAIR_GENES, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_PYRIMIDINE_CONTAINING_COMPOUND_CATABOLIC_PROCESS, GOBP_NUCLEOTIDE_EXCISION_REPAIR, MUELLER_PLURINET, GCM_RING1, GOBP_PYRIMIDINE_NUCLEOTIDE_METABOLIC_PROCESS, GOBP_DNA_MODIFICATION

GO Biological Process (7): base-excision repair, AP site formation (GO:0006285), nucleotide-excision repair (GO:0006289), depyrimidination (GO:0045008), DNA repair (GO:0006281), base-excision repair (GO:0006284), response to stress (GO:0006950), DNA damage response (GO:0006974)

GO Molecular Function (17): oxidized pyrimidine nucleobase lesion DNA N-glycosylase activity (GO:0000703), damaged DNA binding (GO:0003684), double-stranded DNA binding (GO:0003690), DNA-(apurinic or apyrimidinic site) endonuclease activity (GO:0003906), endonuclease activity (GO:0004519), oxidized purine nucleobase lesion DNA N-glycosylase activity (GO:0008534), DNA N-glycosylase activity (GO:0019104), metal ion binding (GO:0046872), 4 iron, 4 sulfur cluster binding (GO:0051539), class I DNA-(apurinic or apyrimidinic site) endonuclease activity (GO:0140078), DNA binding (GO:0003677), catalytic activity (GO:0003824), protein binding (GO:0005515), hydrolase activity (GO:0016787), hydrolase activity, acting on glycosyl bonds (GO:0016798), lyase activity (GO:0016829), iron-sulfur cluster binding (GO:0051536)

GO Cellular Component (3): nucleus (GO:0005634), nucleoplasm (GO:0005654), mitochondrion (GO:0005739)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Depyrimidination	2
Defective Base Excision Repair Associated with NTHL1	2
Resolution of Abasic Sites (AP sites)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA metabolic process	2
DNA repair	2
oxidized base lesion DNA N-glycosylase activity	2
DNA binding	2
catalytic activity	2
intracellular membrane-bounded organelle	2
base-excision repair	1
base-excision repair, AP site formation	1
DNA modification	1
pyrimidine deoxyribonucleotide catabolic process	1
DNA damage response	1
response to stimulus	1
cellular response to stress	1
DNA endonuclease activity	1
nuclease activity	1
hydrolase activity, hydrolyzing N-glycosyl compounds	1
catalytic activity, acting on DNA	1
cation binding	1
iron-sulfur cluster binding	1
DNA-(apurinic or apyrimidinic site) endonuclease activity	1
carbon-oxygen lyase activity	1
nucleic acid binding	1
molecular_function	1
binding	1
hydrolase activity	1
metal cluster binding	1
nuclear lumen	1
cellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

1904 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NTHL1	OGG1	P78554	985
NTHL1	NEIL1	Q96FI4	984
NTHL1	NEIL2	Q969S2	982
NTHL1	XRCC1	P18887	976
NTHL1	NEIL3	Q8TAT5	906
NTHL1	YBX1	P16990	895
NTHL1	MUTYH	Q9UIF7	862
NTHL1	APEX1	P27695	846
NTHL1	UNG	P13051	796
NTHL1	TDG	Q13569	775
NTHL1	MPG	P29372	768
NTHL1	POLD1	P28340	767
NTHL1	POLB	P06746	765
NTHL1	FEN1	P39748	744
NTHL1	POLE	Q07864	744

IntAct

32 interactions, top by confidence:

A	B	Type	Score
MINDY3	UBB	psi-mi:“MI:0914”(association)	0.530
RPL27	NTHL1	psi-mi:“MI:0915”(physical association)	0.400
POU4F1	NTHL1	psi-mi:“MI:0915”(physical association)	0.400
Rpl35	RPS6	psi-mi:“MI:0914”(association)	0.350
RPL10	RPS6	psi-mi:“MI:0914”(association)	0.350
Gspt1	MRPL27	psi-mi:“MI:0914”(association)	0.350
CAMKK1		psi-mi:“MI:0914”(association)	0.350
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
ENG	IGKV2-28	psi-mi:“MI:0914”(association)	0.350
HTRA4	PSMD12	psi-mi:“MI:0914”(association)	0.350
H2BC21	SMCHD1	psi-mi:“MI:0914”(association)	0.350
HMGN5	SMCHD1	psi-mi:“MI:0914”(association)	0.350
NUMA1	SHANK3	psi-mi:“MI:0914”(association)	0.350
ANOS1	ZNF724	psi-mi:“MI:0914”(association)	0.350
PTDSS1	IGLL5	psi-mi:“MI:0914”(association)	0.350
KCNE3	PIK3R2	psi-mi:“MI:0914”(association)	0.350
CYB561D2	TNFRSF10B	psi-mi:“MI:0914”(association)	0.350
EMX2	LRP4	psi-mi:“MI:0914”(association)	0.350
IL31RA	DUSP14	psi-mi:“MI:0914”(association)	0.350
RINL	SERPINB8	psi-mi:“MI:0914”(association)	0.350
SLC16A8	NTHL1	psi-mi:“MI:0914”(association)	0.350
ATF3	C11orf98	psi-mi:“MI:0914”(association)	0.350
CASP3	C11orf98	psi-mi:“MI:0914”(association)	0.350
NTHL1	NUDT1	psi-mi:“MI:0915”(physical association)	0.000
NTHL1		psi-mi:“MI:0915”(physical association)	0.000
NTHL1	RBL1	psi-mi:“MI:0915”(physical association)	0.000
NTHL1	GAPDHS	psi-mi:“MI:0915”(physical association)	0.000
NTHL1	MYH7	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (58): NTHL1 (Affinity Capture-RNA), NTHL1 (Affinity Capture-RNA), NTHL1 (Biochemical Activity), NTHL1 (Affinity Capture-MS), NTHL1 (Affinity Capture-MS), NTHL1 (Affinity Capture-MS), NTHL1 (Affinity Capture-MS), NTHL1 (Affinity Capture-MS), NTHL1 (Affinity Capture-MS), MYH7 (Affinity Capture-MS), NUDT1 (Affinity Capture-MS), MYH4 (Affinity Capture-MS), GAPDHS (Affinity Capture-MS), RNMTL1 (Affinity Capture-MS), ERCC5 (Reconstituted Complex)

ESM2 similar proteins: A0A1D6LAG9, A2RTX5, A6QLY4, A6QNM8, A7M7B9, A9S0B8, A9VB27, B9DFZ0, C1BM18, E2RDZ6, F4JCQ3, G3X8U3, O35980, O70157, O75879, P13051, P36776, P54137, P78549, P97931, Q09907, Q0V9S0, Q13472, Q2KID2, Q4KM92, Q4R380, Q59HJ6, Q5ZKD7, Q640B4, Q7SXA9, Q80UN9, Q80VY9, Q8BLY2, Q8BYM8, Q8CGK3, Q8K582, Q8R5G2, Q8SRB8, Q924S5, Q99JT1

Diamond homologs: A7M7B9, B9DFZ0, C8VC05, O35980, P31378, P39788, P54137, P78549, Q08214, Q09907, Q2KID2, Q4UK93, Q58030, Q8SRB8, Q9SIC4, Q9WYK0, P0AB83, P0AB84, P46303, P57219, P73715, Q89AW4, Q92GH4, O05956, Q05869, Q68W04, P63541, P9WQ10, P9WQ11, O83754, P29588, P44319, Q4J8R2, Q8KA16, Q9CB92, A0R567, O31584, P83847, Q10159, P9WQ08

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
TRIM26	“down-regulates quantity by destabilization”	NTHL1	ubiquitination
CDK1	“up-regulates activity”	NTHL1	phosphorylation
NTHL1	up-regulates	Base-excision_repair

Disease & clinical

Clinical variants and AI predictions

ClinVar

1808 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	114
Likely pathogenic	33
Uncertain significance	950
Likely benign	532
Benign	6

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1068685	NM_002528.7(NTHL1):c.510del (p.Val171fs)	Pathogenic
1070434	NM_002528.7(NTHL1):c.265dup (p.Val89fs)	Pathogenic
1073183	NC_000016.9:g.(?2089925)(2114438_?)del	Pathogenic
1074525	NM_002528.7(NTHL1):c.307dup (p.Asp103fs)	Pathogenic
1074540	NM_002528.7(NTHL1):c.84del (p.Pro30fs)	Pathogenic
1075052	NM_002528.7(NTHL1):c.160_161del (p.Gln54fs)	Pathogenic
1075792	NM_002528.7(NTHL1):c.161dup (p.Arg55fs)	Pathogenic
1076395	NM_002528.7(NTHL1):c.736A>T (p.Lys246Ter)	Pathogenic
1415037	NM_002528.7(NTHL1):c.418dup (p.Ala140fs)	Pathogenic
1425021	NC_000016.10:g.2047835G>A	Pathogenic
1435962	NM_002528.7(NTHL1):c.449dup (p.Leu151fs)	Pathogenic
1441860	NM_002528.7(NTHL1):c.237G>A (p.Trp79Ter)	Pathogenic
1452364	NM_002528.7(NTHL1):c.568C>T (p.Gln190Ter)	Pathogenic
1454268	NC_000016.9:g.(?2089925)(2104451_?)del	Pathogenic
1457084	NM_002528.7(NTHL1):c.726del (p.Arg242fs)	Pathogenic
1457235	NM_002528.7(NTHL1):c.172_175del (p.Val58fs)	Pathogenic
1484387	NM_002528.7(NTHL1):c.675_676del (p.Ser226fs)	Pathogenic
1740398	NM_002528.7(NTHL1):c.417_436dup (p.Leu146fs)	Pathogenic
1741266	NM_002528.7(NTHL1):c.428dup (p.Met143fs)	Pathogenic
1754295	NM_002528.7(NTHL1):c.633dup (p.Lys212fs)	Pathogenic
1776794	NM_002528.7(NTHL1):c.138del (p.Pro46_Val47insTer)	Pathogenic
2020093	NM_002528.7(NTHL1):c.664dup (p.Trp222fs)	Pathogenic
2020379	NM_002528.7(NTHL1):c.666G>A (p.Trp222Ter)	Pathogenic
2020818	NM_002528.7(NTHL1):c.356del (p.Val119fs)	Pathogenic
2025416	NM_002528.7(NTHL1):c.226del (p.Val76fs)	Pathogenic
2084356	NM_002528.7(NTHL1):c.365_371del (p.Tyr122fs)	Pathogenic
2120066	NM_002528.7(NTHL1):c.252G>A (p.Trp84Ter)	Pathogenic
2135297	NM_002528.7(NTHL1):c.469del (p.Leu157fs)	Pathogenic
2423284	NC_000016.9:g.(?2093548)(2113074_?)del	Pathogenic
2423285	NC_000016.9:g.(?2089925)(2105540_?)del	Pathogenic

SpliceAI

1587 predictions. Top by Δscore:

Variant	Effect	Δscore
16:2043559:CTACT:C	donor_loss	1.0000
16:2043561:ACT:A	donor_loss	1.0000
16:2043562:CTC:C	donor_loss	1.0000
16:2043563:TCACC:T	donor_loss	1.0000
16:2043564:CAC:C	donor_loss	1.0000
16:2043565:A:AC	donor_gain	1.0000
16:2043565:ACCA:A	donor_loss	1.0000
16:2043566:C:A	donor_loss	1.0000
16:2043566:C:CC	donor_gain	1.0000
16:2043722:TTGCT:T	acceptor_gain	1.0000
16:2043723:TGCT:T	acceptor_gain	1.0000
16:2043725:CT:C	acceptor_gain	1.0000
16:2043726:TC:T	acceptor_loss	1.0000
16:2043727:C:CC	acceptor_gain	1.0000
16:2043728:T:C	acceptor_loss	1.0000
16:2044624:GCTCA:G	donor_loss	1.0000
16:2044625:CTCA:C	donor_loss	1.0000
16:2044626:TCA:T	donor_loss	1.0000
16:2044628:AC:A	donor_gain	1.0000
16:2044628:ACCCT:A	donor_gain	1.0000
16:2044629:CC:C	donor_gain	1.0000
16:2044629:CCCT:C	donor_gain	1.0000
16:2044629:CCCTC:C	donor_gain	1.0000
16:2044632:T:A	donor_gain	1.0000
16:2046362:CGCTT:C	acceptor_gain	1.0000
16:2046364:CTT:C	acceptor_gain	1.0000
16:2046367:C:CC	acceptor_gain	1.0000
16:2040045:TCCC:T	acceptor_loss	0.9900
16:2040048:C:CA	acceptor_loss	0.9900
16:2040239:C:CC	acceptor_gain	0.9900

AlphaMissense

1959 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:2043721:C:A	K185N	0.990
16:2043721:C:G	K185N	0.990
16:2044636:G:C	F181L	0.989
16:2044636:G:T	F181L	0.989
16:2044638:A:G	F181L	0.989
16:2040197:A:G	W251R	0.987
16:2040197:A:T	W251R	0.987
16:2040232:T:A	D239V	0.985
16:2040231:G:C	D239E	0.984
16:2040231:G:T	D239E	0.984
16:2043616:C:A	K220N	0.982
16:2043616:C:G	K220N	0.982
16:2043697:G:C	S193R	0.981
16:2043697:G:T	S193R	0.981
16:2043699:T:G	S193R	0.981
16:2046197:C:A	R103S	0.976
16:2046197:C:G	R103S	0.976
16:2040225:A:C	H241Q	0.972
16:2040225:A:T	H241Q	0.972
16:2040216:T:A	R244S	0.970
16:2040216:T:G	R244S	0.970
16:2040227:G:C	H241D	0.970
16:2043626:A:T	V217D	0.970
16:2044766:A:T	L138H	0.969
16:2040195:C:A	W251C	0.968
16:2040195:C:G	W251C	0.968
16:2043723:T:C	K185E	0.968
16:2044759:G:C	S140R	0.968
16:2044759:G:T	S140R	0.968
16:2044761:T:G	S140R	0.968

dbSNP variants (sampled 300 via entrez): RS1000035334 (16:2042100 G>A), RS1000122133 (16:2049036 T>C), RS1000139988 (16:2046913 A>G), RS1000524143 (16:2045925 T>A), RS1000576492 (16:2046148 C>A,G,T), RS1000703810 (16:2041668 C>T), RS1000830374 (16:2045395 C>G,T), RS1001117510 (16:2041416 C>T), RS1001385865 (16:2045415 T>G), RS1001704151 (16:2043289 C>T), RS1002333412 (16:2042154 G>A), RS1002532120 (16:2040538 G>C,T), RS1002990126 (16:2040726 G>A), RS1003268934 (16:2043209 C>T), RS1003422958 (16:2047284 C>T)

Disease associations

OMIM: gene MIM:602656 | disease phenotypes: MIM:616415, MIM:613254, MIM:114500, MIM:175100, MIM:606690, MIM:607341, MIM:173900

GenCC curated gene-disease

Disease	Classification	Inheritance
familial adenomatous polyposis 3	Definitive	Autosomal recessive
NTHL1-deficiency tumor predisposition syndrome	Definitive	Autosomal recessive
breast cancer	Limited	Autosomal recessive
meningioma	Limited	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
NTHL1-deficiency tumor predisposition syndrome	Definitive	AR

Mondo (11): hereditary neoplastic syndrome (MONDO:0015356), familial adenomatous polyposis 3 (MONDO:0014630), tuberous sclerosis 2 (MONDO:0013199), colorectal cancer (MONDO:0005575), familial adenomatous polyposis 1 (MONDO:0021056), NTHL1-deficiency tumor predisposition syndrome (MONDO:0100502), lymphangioleiomyomatosis (MONDO:0011705), isolated focal cortical dysplasia type II (MONDO:0011818), polycystic kidney disease 1 (MONDO:0008263), breast cancer (MONDO:0007254), meningioma (MONDO:0016642)

Orphanet (7): Inherited cancer-predisposing syndrome (Orphanet:140162), Attenuated familial adenomatous polyposis (Orphanet:220460), NTHL1-related polyposis (Orphanet:454840), Tuberous sclerosis complex (Orphanet:805), Isolated focal cortical dysplasia type II (Orphanet:268994), Lymphangioleiomyomatosis (Orphanet:538), NON RARE IN EUROPE: Colorectal cancer (Orphanet:466667)

HPO phenotypes

18 total (18 of 18 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000138	Ovarian cyst
HP:0002671	Basal cell carcinoma
HP:0002858	Meningioma
HP:0002860	Squamous cell carcinoma
HP:0003002	Breast carcinoma
HP:0003003	Colon cancer
HP:0003581	Adult onset
HP:0005227	Adenomatous colonic polyposis
HP:0006725	Pancreatic adenocarcinoma
HP:0006771	Duodenal adenocarcinoma
HP:0008069	Neoplasm of the skin
HP:0009725	Bladder neoplasm
HP:0012114	Endometrial carcinoma
HP:0012125	Prostate cancer
HP:0012539	Non-Hodgkin lymphoma
HP:0031287	Seborrheic keratosis
HP:0100743	Neoplasm of the rectum

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST000785_36	Longevity	1.000000e-06
GCST010988_30	Adult body size	2.000000e-09

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D018192	Lymphangioleiomyomatosis	C04.557.375.460.465; C04.557.450.692.500; C15.604.515.562.465; C20.683.515.710.465
D008579	Meningioma	C04.557.580.520; C04.557.645.520; C04.588.614.250.580.500; C10.551.240.500.500
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700
C537067	Focal cortical dysplasia of Taylor (supp.)
C536326	Polycystic kidney disease, type 1 (supp.)
C566021	Tuberous Sclerosis 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523264 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, increases methylation, decreases expression, decreases methylation, increases expression (+1 more)	4
sodium arsenite	affects cotreatment, increases expression, decreases expression	4
Tretinoin	decreases expression	3
cobaltous chloride	decreases expression	2
Acetaminophen	decreases expression	2
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, decreases expression	2
Benzo(a)pyrene	affects methylation	2
Cisplatin	affects cotreatment, increases expression, affects expression, affects reaction	2
Methyl Methanesulfonate	decreases expression	2
Cyclosporine	decreases expression	2
FR900359	decreases phosphorylation	1
bisphenol F	affects cotreatment, increases expression	1
TAK-243	increases sumoylation	1
pradimicin-IRD	decreases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
lead acetate	affects cotreatment, increases expression	1
mono-(2-ethylhexyl)phthalate	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
chromous chloride	affects cotreatment, increases expression	1
chromic oxide	affects cotreatment, increases expression	1
benzo(e)pyrene	decreases methylation	1
coumarin	increases phosphorylation	1
methacrylaldehyde	increases oxidation, increases abundance, affects cotreatment	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
CPG-oligonucleotide	decreases expression	1
K 7174	decreases expression	1
jinfukang	affects cotreatment, increases expression	1
riccardin D	decreases expression	1
NSC 689534	affects binding, decreases expression	1

ChEMBL screening assays

8 unique, capped per target: 7 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4422183	Binding	Inhibition of NTH1 (unknown origin) assessed as remaining enzyme activity at 50 uM incubated for 40 mins by TAMRA fluorescence-based assay	Small molecule inhibitors of 8-oxoguanine dna glycosylase-1 (ogg1)
CHEMBL5665449	Functional	Inhibition of NTHL1 by quantifying inhibition of NTHL1-mediated cleavage and dissociation of quenched duplex DNA oligonucleotides, measured as fluorescence at 594 nm.	Enzyme Inhibitor Single Concentration assay results for EUbOPEN Chemogenomics Library

Cellosaurus cell lines

8 cell lines: 8 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_DX48	HAP1 NTHL1 (-) XPA (-) 1	Cancer cell line	Male
CVCL_DX49	HAP1 NTHL1 (-) XPA (-) 2	Cancer cell line	Male
CVCL_DX50	HAP1 NTHL1 (-) XPA (-) 3	Cancer cell line	Male
CVCL_TB25	HAP1 NTHL1 (-) 1	Cancer cell line	Male
CVCL_TB26	HAP1 NTHL1 (-) 2	Cancer cell line	Male
CVCL_TB27	HAP1 NTHL1 (-) 3	Cancer cell line	Male
CVCL_TB28	HAP1 NTHL1 (-) 4	Cancer cell line	Male
CVCL_TB29	HAP1 NTHL1 (-) 5	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00014638	PHASE4	COMPLETED	Letrozole in Treating Postmenopausal Women With Metastatic Breast Cancer
NCT00022386	PHASE4	COMPLETED	Epoetin Alfa in Treating Chemotherapy-Related Anemia in Women With Stage I, Stage II, or Stage III Breast Cancer
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00030758	PHASE4	UNKNOWN	Filgrastim or Pegfilgrastim in Preventing Neutropenia in Women Receiving Chemotherapy Following Surgery for Breast Cancer
NCT00082277	PHASE4	COMPLETED	Anastrozole Biphosphonate Study in Postmenopausal Women With Hormone-Receptor-Positive Early Breast Cancer
NCT00087620	PHASE4	TERMINATED	A Study of Capecitabine In Combination With Docetaxel vs Capecitabine Followed by Docetaxel As First-Line Treatment For Metastatic Breast Cancer
NCT00121836	PHASE4	COMPLETED	A Study of Xeloda (Capecitabine) in Women With HER2-Negative Metastatic Breast Cancer
NCT00126360	PHASE4	UNKNOWN	STARS Breast Trial (Study of Anastrozole and Radiotherapy Sequencing Pilot)
NCT00127933	PHASE4	COMPLETED	XeNA Study - A Study of Xeloda (Capecitabine) in Patients With Invasive Breast Cancer
NCT00128297	PHASE4	COMPLETED	Pamidronate Administration in Breast Cancer Patients With Bone Metastases
NCT00129597	PHASE4	UNKNOWN	Effect of Ketalar to Prevent Postoperative Chronic Pain After Mastectomy
NCT00131170	PHASE4	COMPLETED	Paravertebral Block for Breast Surgery
NCT00156039	PHASE4	COMPLETED	Randomized Trial of Follow-up Strategies in Breast Cancer
NCT00160901	PHASE4	COMPLETED	Complementary Therapies for the Reduction of Side Effects During Chemotherapy for Breast Cancer
NCT00171847	PHASE4	TERMINATED	Study of the Efficacy and Safety of Letrozole Combined With Trastuzumab in Patients With Metastatic Breast Cancer
NCT00176046	PHASE4	COMPLETED	Mistletoe Extract in Early or Advanced Breast Cancer, A Feasibility Study
NCT00190697	PHASE4	COMPLETED	A Study of LY353381 (Arzoxifene) for Patients Who Benefitted From This Drug in Other Oncology Trials and Wished to Continue Treatment
NCT00234195	PHASE4	COMPLETED	Wellbutrin XL, Major Depressive Disorder and Breast Cancer
NCT00237133	PHASE4	COMPLETED	Treatment of Locally Advanced Breast Cancer With Letrozole in Postmenopausal Women
NCT00237224	PHASE4	COMPLETED	Open Label Study of Postmenopausal Women With ER and /or PgR Positive Breast Cancer Treated With Letrozole
NCT00241046	PHASE4	TERMINATED	Letrozole in the Treatment of 1st and 2nd Line Hormone Receptor Positive Breast Cancer: Pre-therapeutic Risk Assessment
NCT00277160	PHASE4	COMPLETED	A Study of Primary Prophylaxis With Neulasta (Pegfilgrastim) Versus Secondary Prophylaxis After Chemotherapy in Elderly Subjects (>/= 65 Years Old) With Cancer
NCT00323479	PHASE4	COMPLETED	Arthralgia During Anastrozole Therapy for Breast Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00356148	PHASE4	COMPLETED	The Efficacy of Prophylactic Antibiotic Administration During Breast Cancer Surgery in Overweight Patients.
NCT00372476	PHASE4	COMPLETED	Efficacy and Safety of Imatinib and Vinorelbine in Patients With Advanced Breast Cancer
NCT00413491	PHASE4	UNKNOWN	National Screening in Denmark With MR Versus Mammography and Ultrasound of Women With BRCA1 or BRCA2 Mutations
NCT00484614	PHASE4	UNKNOWN	Study the Role of Positron Emission Mammography in Pre-surgical Planning for Breast Cancer
NCT00485953	PHASE4	COMPLETED	Effect of Bisphosphonate on Bone Loss in Postmenopausal Women With Breast Cancer Initiating Aromatase Inhibitor Therapy
NCT00496678	PHASE4	COMPLETED	Trial of Patient Navigation-Activation
NCT00531973	PHASE4	UNKNOWN	A Study of Liposomal Doxorubicin in Women With Breast Cancer Exploiting Tissue Doppler Imaging
NCT00537771	PHASE4	COMPLETED	Liver Safety Under Upfront Arimidex vs Tamoxifen
NCT00544986	PHASE4	COMPLETED	A Prospective,Open-label Study of Anastrozole in Post-menopausal Women With Hormone Sensitive Advanced Breast Cancer
NCT00613275	PHASE4	COMPLETED	Patient Navigation in the Safety Net:CONNECTeDD
NCT00638599	PHASE4	COMPLETED	Comparison of Laryngeal Mask Airway (LMA®) and Tracheal Tube in Modified Radical Mastectomy on Breast Cancer
NCT00647075	PHASE4	UNKNOWN	Yunzhi as Dietary Supplement in Breast Cancer
NCT00688909	PHASE4	COMPLETED	Rheumatological Evaluation of Anastrozole and Letrozole as Adjuvant Treatment in Post-menopausal Women With Breast Cancer
NCT00699101	PHASE4	TERMINATED	Using the Conture® Multi-Lumen Balloon to Deliver Accelerated Partial Breast Brachytherapy
NCT00742222	PHASE4	COMPLETED	Electronic Xoft Intersociety Brachytherapy Trial: Electronic Brachytherapy (EBT) For Treatment of Early Stage Breast Cancer
NCT00754767	PHASE4	TERMINATED	L-Carnitine L-Tartrate in Preventing Peripheral Neuropathy Caused By Chemotherapy in Women With Metastatic Breast Cancer