HPF1

Summary

HPF1 (histone PARylation factor 1, HGNC:26051) is a protein-coding gene on chromosome 4q33, encoding Histone PARylation factor 1 (Q9NWY4). Cofactor for serine ADP-ribosylation that confers serine specificity on PARP1 and PARP2 and plays a key role in DNA damage response.

Enables chromatin binding activity; histone binding activity; and protein ADP-ribosyltransferase-substrate adaptor activity. Involved in DNA repair-dependent chromatin remodeling and double-strand break repair. Located in chromatin and nucleus. Is active in site of DNA damage.

Source: NCBI Gene 54969 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 9 total
• MANE Select transcript: NM_017867

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26051
Approved symbol	HPF1
Name	histone PARylation factor 1
Location	4q33
Locus type	gene with protein product
Status	Approved
Aliases	FLJ20534
Ensembl gene	ENSG00000056050
Ensembl biotype	protein_coding
OMIM	616614
Entrez	54969

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 protein_coding, 2 retained_intron

ENST00000393381, ENST00000506125, ENST00000515204, ENST00000905079, ENST00000905080

RefSeq mRNA: 1 — MANE Select: NM_017867 NM_017867

CCDS: CCDS3813

Canonical transcript exons

ENST00000393381 — 8 exons

Exon	Start	End
ENSE00000740981	169750536	169750725
ENSE00001604754	169741957	169742107
ENSE00001619936	169731704	169731876
ENSE00001653532	169729470	169729709
ENSE00001713210	169757830	169757944
ENSE00001789784	169737660	169737747
ENSE00001800748	169748744	169748842
ENSE00003559667	169753676	169753835

Expression profiles

Bgee: expression breadth ubiquitous, 283 present calls, max score 99.69.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.2075 / max 260.2594, expressed in 1772 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
54813	21.2075	1772

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	99.69	gold quality
secondary oocyte	CL:0000655	99.57	gold quality
choroid plexus epithelium	UBERON:0003911	96.31	gold quality
ganglionic eminence	UBERON:0004023	95.35	gold quality
cortical plate	UBERON:0005343	95.18	gold quality
ventricular zone	UBERON:0003053	94.57	gold quality
embryo	UBERON:0000922	94.42	gold quality
buccal mucosa cell	CL:0002336	94.31	gold quality
pons	UBERON:0000988	94.06	gold quality
hair follicle	UBERON:0002073	93.78	gold quality
germinal epithelium of ovary	UBERON:0001304	92.88	gold quality
skin of hip	UBERON:0001554	92.73	gold quality
Brodmann (1909) area 9	UBERON:0013540	92.68	gold quality
medial globus pallidus	UBERON:0002477	92.30	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	92.15	gold quality
upper leg skin	UBERON:0004262	91.91	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	91.48	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	91.45	gold quality
globus pallidus	UBERON:0001875	91.44	gold quality
trigeminal ganglion	UBERON:0001675	91.41	gold quality
periodontal ligament	UBERON:0008266	91.36	gold quality
amygdala	UBERON:0001876	91.21	gold quality
anterior cingulate cortex	UBERON:0009835	91.07	gold quality
cingulate cortex	UBERON:0003027	91.03	gold quality
tendon of biceps brachii	UBERON:0008188	91.01	gold quality
spinal cord	UBERON:0002240	90.98	gold quality
esophagus squamous epithelium	UBERON:0006920	90.98	gold quality
putamen	UBERON:0001874	90.88	gold quality
substantia nigra	UBERON:0002038	90.76	gold quality
middle temporal gyrus	UBERON:0002771	90.63	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.78

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

20 targeting HPF1, 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-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-513B-5P	99.99	69.96	2150
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-10395-3P	98.10	66.70	1726
HSA-MIR-125B-2-3P	96.69	68.38	1210
HSA-MIR-554	95.20	66.98	341

Literature-anchored findings (GeneRIF, showing 14)

• HPF1/C4orf27 Is a PARP-1-interacting protein that regulates PARP-1 ADP-ribosylation activity in the DNA damage response. (PMID:27067600)
• Serine residues can be ADP-ribosylated by PARP-1 and PARP-2. This serine specificity is conferred by HPF1, a protein that interacts with PARP-1/2. (PMID:28190768)
• Here, the authors show that serine ADP-ribosylation represents the major fraction of ADP-ribosylation synthesized after DNA damage in mammalian cells and that globally serine ADP-ribosylation is dependent on HPF1, PARP1 and ARH3. In the absence of HPF1, glutamate/aspartate becomes the main target residues for ADP-ribosylation. (PMID:29480802)
• HPF1 completes the PARP active site for DNA damage-induced ADP-ribosylation; as HPF1 forms a joint active site with PARP1 or PARP2, our data implicate HPF1 as an important determinant of the response to clinical PARP inhibitors (PMID:32028527)
• Bridging of DNA breaks activates PARP2-HPF1 to modify chromatin. (PMID:32939087)
• Bridging of nucleosome-proximal DNA double-strand breaks by PARP2 enhances its interaction with HPF1. (PMID:33141820)
• HPF1 remodels the active site of PARP1 to enable the serine ADP-ribosylation of histones. (PMID:33589610)
• HPF1 and nucleosomes mediate a dramatic switch in activity of PARP1 from polymerase to hydrolase. (PMID:33683197)
• Serine-linked PARP1 auto-modification controls PARP inhibitor response. (PMID:34210965)
• The regulatory landscape of the human HPF1- and ARH3-dependent ADP-ribosylome. (PMID:34625544)
• Dual function of HPF1 in the modulation of PARP1 and PARP2 activities. (PMID:34732825)
• HPF1 dynamically controls the PARP1/2 balance between initiating and elongating ADP-ribose modifications. (PMID:34795260)
• Germline HPF1 retrogene insertion in RB1 gene involved in cancer predisposition. (PMID:37541786)
• Dispensability of HPF1 for cellular removal of DNA single-strand breaks. (PMID:39162207)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	hpf1	ENSDARG00000057114
mus_musculus	Hpf1	ENSMUSG00000038005
rattus_norvegicus	Hpf1	ENSRNOG00000011293
drosophila_melanogaster	Hpf1	FBGN0037377
caenorhabditis_elegans		WBGENE00010439

Protein

Protein identifiers

Histone PARylation factor 1 — Q9NWY4 (reviewed: Q9NWY4)

All UniProt accessions (1): Q9NWY4

UniProt curated annotations — full annotation on UniProt →

Function. Cofactor for serine ADP-ribosylation that confers serine specificity on PARP1 and PARP2 and plays a key role in DNA damage response. Initiates the repair of double-strand DNA breaks: recruited to DNA damage sites by PARP1 and PARP2 and switches the amino acid specificity of PARP1 and PARP2 from aspartate or glutamate to serine residues, licensing serine ADP-ribosylation of target proteins. Serine ADP-ribosylation of target proteins, such as histones, promotes decompaction of chromatin and the recruitment of repair factors leading to the reparation of DNA strand breaks. Serine ADP-ribosylation of proteins constitutes the primary form of ADP-ribosylation of proteins in response to DNA damage. HPF1 acts by completing the active site of PARP1 and PARP2: forms a composite active site composed of residues from HPF1 and PARP1 or PARP2. While HPF1 promotes the initiation of serine ADP-ribosylation, it restricts the polymerase activity of PARP1 and PARP2 in order to limit the length of poly-ADP-ribose chains. HPF1 also promotes tyrosine ADP-ribosylation, probably by conferring tyrosine specificity on PARP1.

Subunit / interactions. Interacts with PARP1 (via the PARP catalytic domain). Interacts with PARP2 (via the PARP catalytic domain). Interacts with core nucleosomes in a PARP1- and PARP2-dependent manner.

Subcellular location. Chromosome. Nucleus.

Similarity. Belongs to the HPF1 family.

RefSeq proteins (1): NP_060337* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019361	HPF1	Family

Pfam: PF10228

UniProt features (53 total): mutagenesis site 15, helix 15, modified residue 8, turn 5, strand 4, region of interest 2, sequence variant 2, chain 1, active site 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
6M3G	X-RAY DIFFRACTION	1.57
6M3I	X-RAY DIFFRACTION	1.98
6TX2	X-RAY DIFFRACTION	2.09
6TX3	X-RAY DIFFRACTION	2.96
6X0L	ELECTRON MICROSCOPY	3.9
9MJA	ELECTRON MICROSCOPY	4.3
6X0M	ELECTRON MICROSCOPY	6.3
6X0N	ELECTRON MICROSCOPY	10

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NWY4-F1	91.50	0.85

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 (1): 284 (proton donor)

Post-translational modifications (8): 238, 240, 1, 19, 97, 186, 233, 235

Mutagenesis-validated functional residues (15):

Position	Phenotype
149–150	abolished interaction with parp2, leading to destabilize the parp2-nucleosome complex.
179–181	abolished interaction with parp2, leading to destabilize the parp2-nucleosome complex.
238–239	loss of ability to bind parp1 and histones. abolishes parp1 ability to mediate adp-ribosylation.
239	strongly reduced serine adp-ribosylation by parp1 and parp2. decreases parp1 ability to mediate tyrosine adp-ribosylatio
243	does not affect serine adp-ribosylation by parp1 and parp2.
268	promotes auto-adp-ribosylation of parp1. abolished interaction with parp1.
280	promotes auto-adp-ribosylation of parp1.
283	strongly reduced serine adp-ribosylation by parp1 and parp2.
283	promotes auto-adp-ribosylation of parp1. abolished interaction with parp1.
284	abolished serine adp-ribosylation by parp1 and parp2.
285	promotes auto-adp-ribosylation of parp1.
286	strongly reduced serine adp-ribosylation by parp1 and parp2.
292	does not affect serine adp-ribosylation of histones.
303	does not affect serine adp-ribosylation of histones.
307	promotes auto-adp-ribosylation of parp1.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 126 (showing top): XU_GH1_AUTOCRINE_TARGETS_UP, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, GOBP_REGULATION_OF_TRANSFERASE_ACTIVITY, GOLDRATH_ANTIGEN_RESPONSE, GOBP_DNA_DAMAGE_RESPONSE, MARKEY_RB1_ACUTE_LOF_UP, ACEVEDO_LIVER_CANCER_UP, GOBP_CHROMATIN_REMODELING, chr4q33, BERENJENO_TRANSFORMED_BY_RHOA_UP, GOMF_CHROMATIN_BINDING, NUYTTEN_EZH2_TARGETS_DN, GOBP_DNA_METABOLIC_PROCESS, GOMF_HISTONE_BINDING

GO Biological Process (7): DNA repair (GO:0006281), double-strand break repair (GO:0006302), DNA damage response (GO:0006974), regulation of protein ADP-ribosylation (GO:0010835), DNA repair-dependent chromatin remodeling (GO:0140861), protein poly-ADP-ribosylation (GO:0070212), protein localization to chromatin (GO:0071168)

GO Molecular Function (5): chromatin binding (GO:0003682), histone binding (GO:0042393), poly-ADP-D-ribose binding (GO:0072572), protein ADP-ribosyltransferase-substrate adaptor activity (GO:0140768), protein binding (GO:0005515)

GO Cellular Component (4): chromatin (GO:0000785), nucleus (GO:0005634), site of DNA damage (GO:0090734), chromosome (GO:0005694)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA damage response	2
binding	2
chromosome	2
cellular anatomical structure	2
DNA metabolic process	1
DNA repair	1
cellular response to stress	1
regulation of transferase activity	1
NAD+-protein mono-ADP-ribosyltransferase activity	1
chromatin remodeling	1
post-translational protein modification	1
protein localization to chromosome	1
protein binding	1
carbohydrate derivative binding	1
enzyme-substrate adaptor activity	1
intracellular membrane-bounded organelle	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

724 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HPF1	PARP2	Q9UGN5	945
HPF1	ADPRS	Q9NX46	720
HPF1	PARG	Q86W56	704
HPF1	PARP3	Q9Y6F1	628
HPF1	PARP1	P09874	535
HPF1	MACROD1	Q9BQ69	521
HPF1	HMGN1	P05114	508
HPF1	PARP6	Q2NL67	487
HPF1	MACROH2A1	O75367	483
HPF1	MACROD2	A1Z1Q3	465
HPF1	ZC3HAV1	Q7Z2W4	454
HPF1	PARP10	Q53GL7	451
HPF1	PARP11	Q9NR21	444
HPF1	PARP15	Q460N3	441
HPF1	CWC22	Q9HCG8	430

IntAct

32 interactions, top by confidence:

A	B	Type	Score
HPF1	MKLN1	psi-mi:“MI:0915”(physical association)	0.590
KCNJ6	MB21D2	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
HPF1	OCIAD2	psi-mi:“MI:0915”(physical association)	0.400
NFKB1	NFKB1	psi-mi:“MI:0914”(association)	0.350
KCNJ6	HSDL1	psi-mi:“MI:0914”(association)	0.350
PRKCB	HNRNPDL	psi-mi:“MI:0914”(association)	0.350
PRKCB	CHEK1	psi-mi:“MI:0914”(association)	0.350
	ARID1A	psi-mi:“MI:0914”(association)	0.350
FGB	KIF2A	psi-mi:“MI:0914”(association)	0.350
USP47	LAMTOR5	psi-mi:“MI:0914”(association)	0.350
EMX2	LRP4	psi-mi:“MI:0914”(association)	0.350
ARMC6	DDX39A	psi-mi:“MI:0914”(association)	0.350
CHRM4	EXOC5	psi-mi:“MI:0914”(association)	0.350
CHRNB2	SNX2	psi-mi:“MI:0914”(association)	0.350
DNAJC25	TUBAL3	psi-mi:“MI:0914”(association)	0.350
ERF	DVL2	psi-mi:“MI:0914”(association)	0.350
FBXL16	STK25	psi-mi:“MI:0914”(association)	0.350
GSDME	DDX39A	psi-mi:“MI:0914”(association)	0.350
HPN	DDX39A	psi-mi:“MI:0914”(association)	0.350
IL5RA	LETM1	psi-mi:“MI:0914”(association)	0.350
STRIP2	OXSR1	psi-mi:“MI:0914”(association)	0.350
GPKOW	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
ILF3	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
TBRG4	VWA8	psi-mi:“MI:2364”(proximity)	0.270
ZC3H11A	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
NPM1	SBNO1	psi-mi:“MI:2364”(proximity)	0.270
CDH5	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
DSCR9	HPF1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (55): GMPPB (Co-fractionation), PFKM (Co-fractionation), TXN (Co-fractionation), C4orf27 (Affinity Capture-MS), PARP1 (Affinity Capture-MS), HIST2H2AC (Affinity Capture-MS), HIST2H2BE (Affinity Capture-MS), HIST3H3 (Affinity Capture-MS), HIST4H4 (Affinity Capture-MS), H2AFY (Affinity Capture-MS), PARP1 (Affinity Capture-Western), HIST2H2AC (Affinity Capture-Western), H2AFY (Affinity Capture-Western), HIST3H3 (Affinity Capture-Western), PARP2 (Affinity Capture-Western)

ESM2 similar proteins: A1A5P5, A2ARP1, A2VDY4, A7RS11, A8MVJ9, E7EXT2, F6S9E6, O70481, O88554, P06623, P09543, P09874, P0C644, P11103, P18493, P27008, P31669, Q0IHW8, Q14AI0, Q28651, Q32NQ7, Q4R7D0, Q5R5N9, Q5U2Z5, Q60996, Q66I84, Q66JD1, Q68F70, Q6DDS9, Q6GMB0, Q6GQ76, Q7EYV7, Q7SXS8, Q7SYB2, Q8CFE2, Q8CIM8, Q8IWV7, Q93YV6, Q96HW7, Q9BVC3

Diamond homologs: A2VDY4, A7RS11, A8MVJ9, Q7SXS8, Q8CFE2, Q9NWY4, Q9VNI3

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	1
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

2311 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:169731765:T:A	D283V	0.999
4:169731765:T:G	D283A	0.999
4:169731766:C:G	D283H	0.999
4:169731771:G:T	A281D	0.999
4:169731764:A:C	D283E	0.998
4:169731764:A:T	D283E	0.998
4:169731765:T:C	D283G	0.998
4:169731773:A:C	F280L	0.998
4:169731773:A:T	F280L	0.998
4:169731774:A:G	F280S	0.998
4:169731775:A:G	F280L	0.998
4:169731750:C:T	G288D	0.997
4:169731761:T:A	E284D	0.997
4:169731761:T:G	E284D	0.997
4:169731762:T:A	E284V	0.997
4:169731774:A:C	F280C	0.997
4:169737680:C:G	R239P	0.997
4:169737686:C:T	G237E	0.997
4:169729663:A:G	L319P	0.996
4:169731745:C:A	G290W	0.996
4:169731766:C:T	D283N	0.996
4:169737710:A:T	V229D	0.996
4:169731723:A:G	L297P	0.995
4:169731745:C:G	G290R	0.995
4:169731745:C:T	G290R	0.995
4:169731756:T:A	D286V	0.995
4:169731771:G:A	A281V	0.995
4:169731772:C:G	A281P	0.995
4:169731751:C:G	G288R	0.994
4:169731756:T:C	D286G	0.994

dbSNP variants (sampled 300 via entrez): RS10001076 (4:169742618 C>A,G,T), RS1000254589 (4:169731449 A>G), RS1000429053 (4:169737904 T>A), RS1000671257 (4:169736815 C>T), RS1000765703 (4:169736573 C>T), RS1000926485 (4:169748893 C>T), RS10012711 (4:169742608 A>C,G,T), RS1001495859 (4:169755986 T>C), RS10016129 (4:169752695 C>A,T), RS1001662569 (4:169732884 G>A,C), RS10016639 (4:169753185 C>T), RS10018221 (4:169743626 T>C), RS10019257 (4:169744869 A>C), RS10019362 (4:169744965 A>G), RS10019363 (4:169744966 A>C,G)

Disease associations

OMIM: gene MIM:616614 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002539_54	Schizophrenia	1.000000e-09
GCST004521_54	Autism spectrum disorder or schizophrenia	9.000000e-09
GCST006803_41	Schizophrenia	3.000000e-08

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases methylation	3
potassium chromate(VI)	decreases expression, affects cotreatment	2
aristolochic acid I	increases expression, decreases expression	1
GSK-J4	decreases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression, increases abundance	1
cobaltous chloride	decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	decreases expression	1
abrine	decreases expression	1
Resveratrol	increases expression, affects cotreatment	1
Temozolomide	decreases expression	1
Sunitinib	decreases expression	1
Air Pollutants	affects expression, increases abundance	1
Arsenic	decreases expression, increases abundance	1
Benzo(a)pyrene	increases methylation	1
Dimethyl Sulfoxide	increases expression	1
Ivermectin	decreases expression	1
Ozone	affects expression, increases abundance	1
Plant Extracts	affects cotreatment, increases expression	1
Quercetin	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	increases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
Cyclosporine	decreases expression	1
Copper Sulfate	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D8MJ	Ubigene HCT 116 HPF1 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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