PAXX

Summary

PAXX (PAXX non-homologous end joining factor, HGNC:27849) is a protein-coding gene on chromosome 9q34.3, encoding Protein PAXX (Q9BUH6). Non-essential DNA repair protein involved in DNA non-homologous end joining (NHEJ); participates in double-strand break (DSB) repair and V(D)J recombination.

The protein encoded by this gene plays a role in the nonhomologous end joining (NHEJ) pathway of DNA double-strand break repair. The encoded protein may function to stabilize the Ku70/Ku80 heterodimer to facilitate the assembly and maintain the stability of the NHEJ complex.

Source: NCBI Gene 286257 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 10 total

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:27849
Approved symbol	PAXX
Name	PAXX non-homologous end joining factor
Location	9q34.3
Locus type	gene with protein product
Status	Approved
Aliases	XLS
Ensembl gene	ENSG00000148362
OMIM	616315
Entrez	286257

Gene structure

Transcript identifiers

Ensembl transcripts: 0

RefSeq mRNA: 0 — MANE Select: None

Canonical transcript exons

None — 0 exons

Expression profiles

Bgee: expression breadth ubiquitous, 209 present calls, max score 98.53.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	98.53	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	97.03	gold quality
adenohypophysis	UBERON:0002196	96.60	gold quality
mucosa of transverse colon	UBERON:0004991	96.46	gold quality
lower esophagus mucosa	UBERON:0035834	96.27	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.08	gold quality
spleen	UBERON:0002106	95.70	gold quality
cerebellar hemisphere	UBERON:0002245	95.59	gold quality
cerebellar cortex	UBERON:0002129	95.46	gold quality
right lobe of thyroid gland	UBERON:0001119	95.43	gold quality
tibial nerve	UBERON:0001323	95.38	gold quality
right lung	UBERON:0002167	95.17	gold quality
spinal cord	UBERON:0002240	94.98	gold quality
right frontal lobe	UBERON:0002810	94.97	gold quality
anterior cingulate cortex	UBERON:0009835	94.96	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	94.76	gold quality
pituitary gland	UBERON:0000007	94.74	gold quality
apex of heart	UBERON:0002098	94.53	gold quality
left lobe of thyroid gland	UBERON:0001120	94.51	gold quality
amygdala	UBERON:0001876	94.49	gold quality
endocervix	UBERON:0000458	94.42	gold quality
hypothalamus	UBERON:0001898	94.40	gold quality
Brodmann (1909) area 9	UBERON:0013540	94.40	gold quality
left uterine tube	UBERON:0001303	94.37	gold quality
putamen	UBERON:0001874	94.23	gold quality
body of stomach	UBERON:0001161	94.22	gold quality
small intestine Peyer’s patch	UBERON:0003454	94.15	gold quality
right lobe of liver	UBERON:0001114	94.11	gold quality
body of pancreas	UBERON:0001150	94.10	gold quality
cerebellum	UBERON:0002037	93.99	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 9.

Experiment	Marker?	Max mean expression
E-GEOD-106540	yes	872.23
E-CURD-122	yes	45.10
E-MTAB-9467	yes	32.01
E-HCAD-1	yes	13.45
E-MTAB-8498	yes	13.04
E-MTAB-10042	yes	11.58
E-MTAB-8410	yes	8.96
E-ANND-3	yes	8.09
E-MTAB-9801	yes	5.81
E-CURD-120	no	5.94

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

12 targeting PAXX, 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-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4689	96.97	65.79	1209
HSA-MIR-6858-5P	96.05	64.59	1020
HSA-MIR-6726-5P	95.97	63.72	841
HSA-MIR-920	95.97	63.95	811
HSA-MIR-4300	95.85	64.56	1003
HSA-MIR-5591-5P	95.85	64.76	1002

Literature-anchored findings (GeneRIF, showing 8)

• PAXX promotes Ku-dependent DNA ligation in vitro and assembly of core nonhomologous end-joining (NHEJ) factors on damaged chromatin in cells. These findings identify PAXX as a new component of the NHEJ machinery. (PMID:25574025)
• These data identify PAXX as a new Non-homologous end joining factor. (PMID:25670504)
• Although PAXX-deficient cells lack c-NHEJ phenotypes, PAXX forms a stable ternary complex with Ku bound to DNA. Thus, PAXX plays an accessory role during c-NHEJ that is largely overlapped by XLF’s function. (PMID:27705800)
• PAXX contributes to base excision repair pathway via interaction of polymerase beta. PAXX deficiency causes TMZ sensitivity. (PMID:30238427)
• PAXX, XLF and XRCC4 synergise in the efficient DNA double-strand breaks recruitment, substrate recognition and stimulation of Pol lambda enzymatic activity during nonhomologous end joining DNA repair. (PMID:30250067)
• Synthetic lethality between DNA repair factors Xlf and Paxx is rescued by inactivation of Trp53 (PMID:30579708)
• Absence of XRCC4 and its paralogs in human cells reveal differences in outcomes for DNA repair and V(D)J recombination. (PMID:31731258)
• PAXX binding to the NHEJ machinery explains functional redundancy with XLF. (PMID:37256950)

Cross-species orthologs

0 orthologs

Protein

Protein identifiers

Protein PAXX — Q9BUH6 (reviewed: Q9BUH6)

Alternative names: Paralog of XRCC4 and XLF, XRCC4-like small protein

All UniProt accessions (0):

UniProt curated annotations — full annotation on UniProt →

Function. Non-essential DNA repair protein involved in DNA non-homologous end joining (NHEJ); participates in double-strand break (DSB) repair and V(D)J recombination. May act as a scaffold required for accumulation of the Ku heterodimer, composed of XRCC5/Ku80 and XRCC6/Ku70, at double-strand break sites and promote the assembly and/or stability of the NHEJ machinery. Involved in NHEJ by promoting the ligation of blunt-ended DNA ends. Together with NHEJ1/XLF, collaborates with DNA polymerase lambda (POLL) to promote joining of non-cohesive DNA ends. Constitutes a non-essential component of classical NHEJ: has a complementary but distinct function with NHEJ1/XLF in DNA repair. Able to restrict infection by herpesvirus 1 (HSV-1) via an unknown mechanism.

Subunit / interactions. Homodimer. Interacts with the DNA-bound XRCC5/Ku80 and XRCC6/Ku70 heterodimer (Ku complex); the interaction is direct. Associated component of the non-homologous end joining (NHEJ) complex, composed of the core proteins PRKDC, LIG4, XRCC4, XRCC6/Ku70, XRCC5/Ku86 and NHEJ1/XLF. Interacts with POLL (DNA polymerase lambda); promoting POLL recruitment to double-strand breaks (DSBs) and stimulation of the end-filling activity of POLL.

Subcellular location. Nucleus. Chromosome Cytoplasm.

Post-translational modifications. Phosphorylation may inhibit interaction with the DNA-bound XRCC5/Ku80 and XRCC6/Ku70 heterodimer (Ku complex).

Domain organisation. The N-terminus (residues 1-113) forms a head domain that is structurally related to those of XRCC4, XLF/NHEJ1, and SASS6.

Similarity. Belongs to the XRCC4-XLF family. PAXX subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9BUH6-1	1	yes
Q9BUH6-2	2

RefSeq proteins (0): (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR027873	PAXX	Family
IPR054134	PAXX_N	Domain

Pfam: PF15384

UniProt features (35 total): strand 11, mutagenesis site 10, modified residue 4, helix 3, splice variant 2, region of interest 2, chain 1, domain 1, short sequence motif 1

Structure

Experimental structures (PDB)

20 structures.

PDB	Method	Resolution (Å)
3WTD	X-RAY DIFFRACTION	2.35
4WJA	X-RAY DIFFRACTION	2.6
7ZYG	ELECTRON MICROSCOPY	2.68
7ZWA	ELECTRON MICROSCOPY	2.8
9CQ3	ELECTRON MICROSCOPY	2.8
9GYF	ELECTRON MICROSCOPY	2.8
9N81	ELECTRON MICROSCOPY	2.8
8ASC	X-RAY DIFFRACTION	2.95
9CQ6	ELECTRON MICROSCOPY	3.1
9N83	ELECTRON MICROSCOPY	3.1
9N82	ELECTRON MICROSCOPY	3.3
9CQC	ELECTRON MICROSCOPY	3.4
3WTF	X-RAY DIFFRACTION	3.45
9GD7	ELECTRON MICROSCOPY	4.25
8EZA	ELECTRON MICROSCOPY	4.39
8BHV	ELECTRON MICROSCOPY	4.51
8BH3	ELECTRON MICROSCOPY	4.55
9G9L	ELECTRON MICROSCOPY	4.63
8BHY	ELECTRON MICROSCOPY	5.33
8EZB	ELECTRON MICROSCOPY	8.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BUH6-F1	83.25	0.60

Functional residue map

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

Post-translational modifications (4): 134, 145, 148, 152

Mutagenesis-validated functional residues (10):

Position	Phenotype
96–109	loss of function in dna non-homologous end joining (nhej).
134	does not affect interaction with the dna-bound xrcc5/ku80 and xrcc6/ku70 heterodimer; when associated with 145-d–152.
134	phospho-mimetic mutant; abolished interaction with dna-bound the dna-bound xrcc5/ku80 and xrcc6/ku70 heterodimer; when a
145–152	does not affect interaction with the dna-bound xrcc5/ku80 and xrcc6/ku70 heterodimer; when associated with a-134.
145–152	phospho-mimetic mutant; abolished interaction with the dna-bound xrcc5/ku80 and xrcc6/ku70 heterodimer; when associated
177–179	abolishes the association with the non-homologous end joining complex. abolished interaction with xrcc6/ku70.
184	abolished interaction with xrcc5/ku80 and xrcc6/ku70.
186–187	abolishes the association with the non-homologous end joining complex.
199–201	abolished interaction with xrcc5/ku80 and xrcc6/ku70.
201	abolishes the association with the non-homologous end joining complex and localization to double-strand break sites. abo

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 68 (showing top): GOBP_DNA_DAMAGE_RESPONSE, ALONSO_METASTASIS_DN, GOCC_DNA_REPAIR_COMPLEX, GOCC_SITE_OF_DOUBLE_STRAND_BREAK, GOBP_DNA_METABOLIC_PROCESS, GOMF_PROTEIN_DIMERIZATION_ACTIVITY, GOMF_PROTEIN_HOMODIMERIZATION_ACTIVITY, GOBP_DNA_REPAIR, GOMF_DNA_POLYMERASE_BINDING, MARTENS_TRETINOIN_RESPONSE_UP, CHANGOLKAR_H2AFY_TARGETS_DN, WAKABAYASHI_ADIPOGENESIS_PPARG_BOUND_8D, GOCC_NONHOMOLOGOUS_END_JOINING_COMPLEX, GOCC_SITE_OF_DNA_DAMAGE, chr9q34

GO Biological Process (2): double-strand break repair via nonhomologous end joining (GO:0006303), DNA damage response (GO:0006974)

GO Molecular Function (4): identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), molecular adaptor activity (GO:0060090), DNA polymerase binding (GO:0070182)

GO Cellular Component (5): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), site of double-strand break (GO:0035861), nonhomologous end joining complex (GO:0070419)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
double-strand break repair	1
cellular response to stress	1
protein binding	1
identical protein binding	1
protein dimerization activity	1
molecular_function	1
binding	1
enzyme binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
site of DNA damage	1
intracellular protein-containing complex	1
DNA repair complex	1

Protein interactions and networks

STRING

598 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PAXX	NHEJ1	Q9H9Q4	997
PAXX	XRCC4	Q13426	995
PAXX	XRCC6	P12956	977
PAXX	XRCC5	P13010	957
PAXX	PRKDC	P78527	949
PAXX	LIG4	P49917	847
PAXX	PNKP	Q96T60	835
PAXX	APTX	Q7Z2E3	834
PAXX	APLF	Q8IW19	721
PAXX	CYREN	Q9BWK5	686
PAXX	WRN	Q14191	632
PAXX	POLM	Q9NP87	604
PAXX	POLL	Q9UGP5	597
PAXX	SHLD2	Q86V20	572
PAXX	TP53BP1	Q12888	537

IntAct

37 interactions, top by confidence:

A	B	Type	Score
XRCC6	XRCC5	psi-mi:“MI:0914”(association)	0.970
NHEJ1	XRCC5	psi-mi:“MI:0915”(physical association)	0.710
XRCC5	PAXX	psi-mi:“MI:0915”(physical association)	0.560
PAXX	OPTN	psi-mi:“MI:0915”(physical association)	0.560
PAXX	XRCC5	psi-mi:“MI:0914”(association)	0.560
GCSH	LIAS	psi-mi:“MI:0914”(association)	0.530
PAXX	WRN	psi-mi:“MI:0914”(association)	0.530
XRCC4	PAXX	psi-mi:“MI:0915”(physical association)	0.400
CD81	HIP1R	psi-mi:“MI:0914”(association)	0.350
XRCC6	ANKRD28	psi-mi:“MI:0914”(association)	0.350
FOXB1	MACROH2A1	psi-mi:“MI:0914”(association)	0.350
IQCF1	TBC1D4	psi-mi:“MI:0914”(association)	0.350
VASH1	AMY1A	psi-mi:“MI:0914”(association)	0.350
PPM1B	BPGM	psi-mi:“MI:0914”(association)	0.350
S100A2	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
IFNAR1	TNFRSF10B	psi-mi:“MI:0914”(association)	0.350
EMX2	LRP4	psi-mi:“MI:0914”(association)	0.350
DLX6	SCGB2A1	psi-mi:“MI:0914”(association)	0.350
RBPMS2	MYCBP2	psi-mi:“MI:0914”(association)	0.350
GAGE1	UBB	psi-mi:“MI:0914”(association)	0.350
RELA	CLTCL1	psi-mi:“MI:0914”(association)	0.350
ZCCHC10	C1orf226	psi-mi:“MI:0914”(association)	0.350
GPX7	HS3ST1	psi-mi:“MI:0914”(association)	0.350
ROPN1	PPM1B	psi-mi:“MI:0914”(association)	0.350
PAXX	TACC2	psi-mi:“MI:0914”(association)	0.350
MRPL21	RPL3	psi-mi:“MI:0914”(association)	0.350
PPM1B		psi-mi:“MI:0914”(association)	0.350

BioGRID (43): C9orf142 (Affinity Capture-MS), C9orf142 (Affinity Capture-MS), C9orf142 (Affinity Capture-MS), C9orf142 (Affinity Capture-MS), C9orf142 (Affinity Capture-MS), C9orf142 (Affinity Capture-MS), C9orf142 (Affinity Capture-MS), C9orf142 (Reconstituted Complex), C9orf142 (Affinity Capture-MS), C9orf142 (Affinity Capture-MS), C9orf142 (Affinity Capture-MS), C9orf142 (Affinity Capture-MS), C9orf142 (Affinity Capture-MS), C9orf142 (Affinity Capture-MS), C9orf142 (Affinity Capture-MS)

ESM2 similar proteins: A1L515, A5PJC7, A8VU90, E1BDF2, O88995, O95153, P0CG25, Q0IIA6, Q0X0E2, Q2TA57, Q3B7L1, Q3U5Q7, Q3UR97, Q3UV16, Q400G9, Q5EBM0, Q5EBP3, Q5PQP9, Q5TM19, Q5U4P2, Q6ZVH7, Q7L591, Q810I0, Q861W0, Q86SX3, Q86UR1, Q86XT2, Q8BNN1, Q8C0R7, Q8IUW3, Q8N398, Q8N4Y2, Q8NAC3, Q8NAG6, Q8R2H1, Q8TE82, Q8VCE9, Q91WA6, Q969T3, Q96BM1

Diamond homologs: Q8K0Y7, Q9BUH6

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	0
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

708 predictions. Top by Δscore:

Variant	Effect	Δscore
9:136992521:G:T	donor_gain	1.0000
9:136992526:A:T	donor_gain	1.0000
9:136992563:G:GG	donor_gain	1.0000
9:136993242:AG:A	donor_loss	1.0000
9:136993243:GGTA:G	donor_loss	1.0000
9:136993244:GTAGG:G	donor_loss	1.0000
9:136993245:T:G	donor_loss	1.0000
9:136993341:A:AC	acceptor_loss	1.0000
9:136993341:A:AG	acceptor_gain	1.0000
9:136993342:G:GT	acceptor_gain	1.0000
9:136993342:GCT:G	acceptor_gain	1.0000
9:136993578:A:AG	acceptor_gain	1.0000
9:136993579:G:GG	acceptor_gain	1.0000
9:136992521:G:GT	donor_gain	0.9900
9:136992558:CTCTA:C	donor_gain	0.9900
9:136992559:TCTA:T	donor_gain	0.9900
9:136992561:TA:T	donor_gain	0.9900
9:136992561:TAGT:T	donor_loss	0.9900
9:136992562:AGT:A	donor_loss	0.9900
9:136992563:GTGA:G	donor_loss	0.9900
9:136992564:T:G	donor_loss	0.9900
9:136992701:G:GG	donor_gain	0.9900
9:136992823:T:TA	donor_gain	0.9900
9:136992824:A:AA	donor_gain	0.9900
9:136993241:C:T	donor_gain	0.9900
9:136993341:AGCT:A	acceptor_gain	0.9900
9:136993342:GC:G	acceptor_gain	0.9900
9:136993342:GCTG:G	acceptor_gain	0.9900
9:136993342:GCTGC:G	acceptor_gain	0.9900
9:136993344:T:A	acceptor_gain	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000031872 (9:136994144 G>A), RS1000721121 (9:136990511 G>A), RS1000786005 (9:136991966 C>T), RS1001604266 (9:136991161 CAGG>C), RS1001676081 (9:136992491 G>A,C,T), RS1001707381 (9:136992873 C>G), RS1003353451 (9:136991469 C>G,T), RS1003384636 (9:136991665 C>T), RS1004566603 (9:136991714 C>T), RS1004847007 (9:136993808 G>A,T), RS1005371154 (9:136993551 G>A), RS1006113949 (9:136990454 T>C), RS1007750028 (9:136991994 G>A), RS1007802213 (9:136992247 A>ACC), RS1008139626 (9:136991027 G>A,T)

Disease associations

OMIM: gene MIM:616315 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	5
bisphenol A	increases expression, affects cotreatment	2
Arsenic	affects cotreatment, decreases expression, increases abundance, increases expression	2
FR900359	affects phosphorylation	1
bisphenol F	affects cotreatment, increases expression	1
zinc chromate	decreases expression, increases abundance	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	decreases expression, increases abundance	1
K 7174	decreases expression	1
jinfukang	increases expression	1
Benzo(a)pyrene	increases methylation	1
Coumestrol	increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Indomethacin	affects cotreatment, increases expression	1
Ivermectin	decreases expression	1
Manganese	increases abundance, affects cotreatment, decreases expression	1
Methyl Methanesulfonate	increases expression	1
Silicon Dioxide	increases expression	1
Smoke	decreases expression	1
Thiram	decreases expression	1
Valproic Acid	increases methylation	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_DX08	HAP1 PRKDC (-) PAXX (-)	Cancer cell line	Male
CVCL_SG37	HAP1 C9orf142 (-) 1	Cancer cell line	Male
CVCL_SG38	HAP1 C9orf142 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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