Q8IW19 (APLF_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Aprataxin and PNK-like factor
EC=4.2.99.18

Alternative name(s):
Apurinic-apyrimidinic endonuclease APLF
PNK and APTX-like FHA domain-containing protein
XRCC1-interacting protein 1

Gene names

Name:	APLF
Synonyms:	C2orf13, PALF, XIP1

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	511 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Nuclease involved in single-strand and double-strand DNA break repair. Recruited to sites of DNA damage through interaction with poly(ADP-ribose), a polymeric post-translational modification synthesized transiently at sites of chromosomal damage to accelerate DNA strand break repair reactions. Displays apurinic-apyrimidinic (AP) endonuclease and 3'-5' exonuclease activities in vitro. Also able to introduce nicks at hydroxyuracil and other types of pyrimidine base damage. Ref.4 Ref.6
Catalytic activity	The C-O-P bond 3' to the apurinic or apyrimidinic site in DNA is broken by a beta-elimination reaction, leaving a 3'-terminal unsaturated sugar and a product with a terminal 5'-phosphate. Ref.4
Subunit structure	Interacts with LIG4, PARP1, XRCC1, XRCC4 and XRCC5. Ref.4 Ref.5 Ref.6 Ref.7
Subcellular location	Nucleus. Cytoplasm › cytosol. Note: Localizes to DNA damage sites. Accumulates at single-strand breaks and double-strand breaks via the PBZ-type zinc fingers. Ref.4 Ref.5 Ref.6 Ref.8 Ref.9
Domain	The PBZ-type zinc fingers (also named CYR) mediate non-covalent poly(ADP-ribose)-binding. Poly(ADP-ribose)-binding is dependent on the presence of zinc and promotes its recruitment to DNA damage sites. Ref.9 The FHA-like domain mediates interaction with XRCC1 and XRCC4. Ref.9
Post-translational modification	Poly-ADP-ribosylated. In addition to binding non covalently poly(ADP-ribose) via its PBZ-type zinc fingers, the protein is also covalently poly-ADP-ribosylated by PARP1. Ref.4 Ref.9 Phosphorylated in an ATM-dependent manner upon double-strand DNA break. Ref.5 Ref.6 Ref.7
Sequence similarities	Belongs to the APLF family. Contains 1 FHA-like domain. Contains 2 PBZ-type zinc fingers.
Sequence caution	The sequence AAY14945.1 differs from that shown. Reason: Erroneous initiation.

Ontologies

Keywords
Biological process	DNA damage DNA repair
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Polymorphism
Domain	Coiled coil Repeat Zinc-finger
Ligand	Metal-binding Nucleotide-binding Zinc
Molecular function	Lyase
PTM	ADP-ribosylation Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	double-strand break repair Inferred from mutant phenotype Ref.4. Source: UniProtKB single strand break repair Inferred from mutant phenotype Ref.4. Source: UniProtKB
Cellular_component	cytosol Inferred from electronic annotation. Source: UniProtKB-SubCell nucleus Inferred from direct assay Ref.4Ref.9. Source: UniProtKB
Molecular_function	3'-5' exonuclease activity Inferred from direct assay Ref.4. Source: UniProtKB DNA-(apurinic or apyrimidinic site) lyase activity Inferred from direct assay Ref.4. Source: UniProtKB endodeoxyribonuclease activity Inferred from direct assay Ref.4. Source: UniProtKB metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW nucleotide binding Inferred from direct assay Ref.9. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
XRCC1	P18887	7	EBI-1256044,EBI-947466

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 511

511

Aprataxin and PNK-like factor

PRO_0000089342

Regions

Domain

1 – 108

108

FHA-like

Zinc finger

377 – 398

22

PBZ-type 1

Zinc finger

419 – 440

22

PBZ-type 2

Region

406 – 416

11

Flexible linker

Coiled coil

487 – 511

25

Potential

Sites

Binding site

376

1

Poly-ADP-ribose

Binding site

381

1

Poly-ADP-ribose

Binding site

386

1

Poly-ADP-ribose

Binding site

387

1

Poly-ADP-ribose

Binding site

423

1

Poly-ADP-ribose

Binding site

428

1

Poly-ADP-ribose

Binding site

429

1

Poly-ADP-ribose

Amino acid modifications

Modified residue

116

1

Phosphoserine; by ATM Ref.5

Natural variations

Natural variant

100

1

I → V.
Corresponds to variant rs11902811 [ dbSNP | Ensembl ].

VAR_032299

Natural variant

224

1

S → T.
Corresponds to variant rs35002937 [ dbSNP | Ensembl ].

VAR_061557

Natural variant

336

1

L → F.
Corresponds to variant rs13404469 [ dbSNP | Ensembl ].

VAR_032300

Experimental info

Mutagenesis

116

1

S → A: Decreases phosphorylation by ATM. Ref.5

Mutagenesis

376

1

R → A: Abolishes poly(ADP-ribose)-binding and poly-ADP-ribosylation by PARP1; when associated with A-421 and A-427. Ref.9

Mutagenesis

379

1

C → A: Abolishes poly(ADP-ribose)-binding and poly-ADP-ribosylation by PARP1; when associated with A-385; A-421 and A-427. Ref.9

Mutagenesis

385

1

C → A: Abolishes poly(ADP-ribose)-binding and poly-ADP-ribosylation by PARP1; when associated with A-379; A-421 and A-427. Ref.9

Mutagenesis

421

1

C → A: Abolishes poly(ADP-ribose)-binding and poly-ADP-ribosylation by PARP1; when associated with A-379; A-385 and A-427. Abolishes poly(ADP-ribose)-binding and poly-ADP-ribosylation by PARP1; when associated with A-376 and A-427. Ref.9

Mutagenesis

427

1

C → A: Abolishes poly(ADP-ribose)-binding and poly-ADP-ribosylation by PARP1; when associated with A-379; A-385 and A-421. Abolishes poly(ADP-ribose)-binding and poly-ADP-ribosylation by PARP1; when associated with A-376 and A-421. Ref.9

Sequence conflict

313

1

Missing in BAF83530. Ref.1

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

511

Helix Strand Turn

Details...

Beta strand

371 – 374

4

Turn

380 – 383

4

Helix

392 – 395

4

Turn

412 – 414

3

Helix

424 – 426

3

Helix

432 – 437

6

Sequences

	Sequence		Length	Mass (Da)
	Q8IW19 [UniParc]. Last modified March 1, 2003. Version 1. Checksum: CBBF0096843298DA	FASTA	511	56,956
	10 20 30 40 50 60 MSGGFELQPR DGGPRVALAP GETVIGRGPL LGITDKRVSR RHAILEVAGG QLRIKPIHTN 70 80 90 100 110 120 PCFYQSSEKS QLLPLKPNLW CYLNPGDSFS LLVDKYIFRI LSIPSEVEMQ CTLRNSQVLD 130 140 150 160 170 180 EDNILNETPK SPVINLPHET TGASQLEGST EIAKTQMTPT NSVSFLGENR DCNKQQPILA 190 200 210 220 230 240 ERKRILPTWM LAEHLSDQNL SVPAISGGNV IQGSGKEEIC KDKSQLNTTQ QGRRQLISSG 250 260 270 280 290 300 SSENTSAEQD TGEECKNTDQ EESTISSKEM PQSFSAITLS NTEMNNIKTN AQRNKLPIEE 310 320 330 340 350 360 LGKVSKHKIA TKRTPHKEDE AMSCSENCSS AQGDSLQDES QGSHSESSSN PSNPETLHAK 370 380 390 400 410 420 ATDSVLQGSE GNKVKRTSCM YGANCYRKNP VHFQHFSHPG DSDYGGVQIV GQDETDDRPE 430 440 450 460 470 480 CPYGPSCYRK NPQHKIEYRH NTLPVRNVLD EDNDNVGQPN EYDLNDSFLD DEEEDYEPTD 490 500 510 EDSDWEPGKE DEEKEDVEEL LKEAKRFMKR K

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Liver.
[2]	"Generation and annotation of the DNA sequences of human chromosomes 2 and 4." Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., Du H. , Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., Wilson R.K. Nature 434:724-731(2005) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[3]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Testis.
[4]	"A novel human AP endonuclease with conserved zinc-finger-like motifs involved in DNA strand break responses." Kanno S., Kuzuoka H., Sasao S., Hong Z., Lan L., Nakajima S., Yasui A. EMBO J. 26:2094-2103(2007) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, POLY-ADP-RIBOSYLATION, INTERACTION WITH LIG4; PARP1; XRCC4 AND XRCC5.
[5]	"Human Xip1 (C2orf13) is a novel regulator of cellular responses to DNA strand breaks." Bekker-Jensen S., Fugger K., Danielsen J.R., Gromova I., Sehested M., Celis J., Bartek J., Lukas J., Mailand N. J. Biol. Chem. 282:19638-19643(2007) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION, INTERACTION WITH XRCC1, PHOSPHORYLATION AT SER-116, MUTAGENESIS OF SER-116.
[6]	"APLF (C2orf13) is a novel human protein involved in the cellular response to chromosomal DNA strand breaks." Iles N., Rulten S., El-Khamisy S.F., Caldecott K.W. Mol. Cell. Biol. 27:3793-3803(2007) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH PARP1; XRCC1; XRCC4 AND XRCC5, SUBCELLULAR LOCATION, PHOSPHORYLATION.
[7]	"APLF (C2orf13) facilitates nonhomologous end-joining and undergoes ATM-dependent hyperphosphorylation following ionizing radiation." Macrae C.J., McCulloch R.D., Ylanko J., Durocher D., Koch C.A. DNA Repair 7:292-302(2008) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH XRCC4, PHOSPHORYLATION.
[8]	"APLF (C2orf13) is a novel component of poly(ADP-ribose) signaling in mammalian cells." Rulten S.L., Cortes-Ledesma F., Guo L., Iles N.J., Caldecott K.W. Mol. Cell. Biol. 28:4620-4628(2008) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION, ADP-RIBOSE-BINDING.
[9]	"Poly(ADP-ribose)-binding zinc finger motifs in DNA repair/checkpoint proteins." Ahel I., Ahel D., Matsusaka T., Clark A.J., Pines J., Boulton S.J., West S.C. Nature 451:81-85(2008) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION, DOMAIN PBZ-TYPE, POLY-ADP-RIBOSYLATION, ADP-RIBOSE-BINDING, MUTAGENESIS OF ARG-376; CYS-379; CYS-385; CYS-421 AND CYS-427.
[10]	"Solution structures of the two PBZ domains from human APLF and their interaction with poly(ADP-ribose)." Eustermann S., Brockmann C., Mehrotra P.V., Yang J.C., Loakes D., West S.C., Ahel I., Neuhaus D. Nat. Struct. Mol. Biol. 17:241-243(2010) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF 368-451 ALONE AND IN COMPLEX WITH ADP-RIBOSE ANALOG, POLY-ADP-RIBOSE BINDING SITES.
[11]	"Structure and identification of ADP-ribose recognition motifs of APLF and role in the DNA damage response." Li G.Y., McCulloch R.D., Fenton A.L., Cheung M., Meng L., Ikura M., Koch C.A. Proc. Natl. Acad. Sci. U.S.A. 107:9129-9134(2010) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF 360-448, LINKER REGION, POLY-ADP-RIBOSE BINDING SITES.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AK290841 mRNA. Translation: BAF83530.1.
AC105054 Genomic DNA. Translation: AAY24113.1.
AC127383 Genomic DNA. Translation: AAY24008.1.
AC130709 Genomic DNA. Translation: AAY14945.1. Different initiation.
BC041144 mRNA. Translation: AAH41144.1.

IPI

IPI00217108.

RefSeq

NP_775816.1. NM_173545.2.

UniGene

Hs.720369.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2KQB	NMR	-	A	368-451	[»]
2KQC	NMR	-	A	368-451	[»]
2KQD	NMR	-	A	368-451	[»]
2KQE	NMR	-	A	368-451	[»]
2KUO	NMR	-	A	360-448	[»]

ProteinModelPortal

Q8IW19.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-39136N.

IntAct

Q8IW19. 3 interactions.

MINT

MINT-3037419.

STRING

9606.ENSP00000307004.

PTM databases

PhosphoSite

Q8IW19.

Polymorphism databases

DMDM

73619699.

Proteomic databases

PaxDb

Q8IW19.

PRIDE

Q8IW19.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000303795; ENSP00000307004; ENSG00000169621.

GeneID

200558.

KEGG

hsa:200558.

UCSC

uc002sep.3. human.

Organism-specific databases

CTD

200558.

GeneCards

GC02P068694.

HGNC

HGNC:28724. APLF.

HPA

HPA034643.

MIM

611035. gene.

neXtProt

NX_Q8IW19.

PharmGKB

PA164715842.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG85452.

HOGENOM

HOG000033995.

HOVERGEN

HBG095728.

InParanoid

Q8IW19.

KO

K13295.

OMA

ECTLRNS.

OrthoDB

EOG4Q8501.

PhylomeDB

Q8IW19.

Gene expression databases

ArrayExpress

Q8IW19.

Bgee

Q8IW19.

CleanEx

HS_APLF.

Genevestigator

Q8IW19.

GermOnline

ENSG00000169621. Homo sapiens.

Family and domain databases

Gene3D

2.60.200.20. 1 hit.

InterPro

IPR000253. FHA_dom.
IPR008984. SMAD_FHA_domain.
IPR019406. Znf_C2H2_APLF-like.
[Graphical view]

Pfam

PF10283. zf-CCHH. 2 hits.
[Graphical view]

SUPFAM

SSF49879. SMAD_FHA. 1 hit.

ProtoNet

Search...

Other

ChiTaRS

APLF. human.

EvolutionaryTrace

Q8IW19.

GenomeRNAi

200558.

NextBio

89940.

SOURCE

Search...

Entry information

Entry name

APLF_HUMAN

Accession

Primary (citable) accession number: Q8IW19
Secondary accession number(s): A8K476 , Q53P47, Q53PB9, Q53QU0

Entry history

Integrated into UniProtKB/Swiss-Prot:	August 16, 2005
Last sequence update:	March 1, 2003
Last modified:	May 1, 2013
This is version 87 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.