O76064 (RNF8_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
E3 ubiquitin-protein ligase RNF8
Short name=hRNF8
EC=6.3.2.-

Alternative name(s):
RING finger protein 8

Gene names

Name:	RNF8
Synonyms:	KIAA0646

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	485 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	E3 ubiquitin-protein ligase that plays a key role in DNA damage signaling via 2 distinct roles: by mediating the 'Lys-63'-linked ubiquitination of histones H2A and H2AX and promoting the recruitment of DNA repair proteins at double-strand breaks (DSBs) sites, and by catalyzing 'Lys-48'-linked ubiquitination to remove target proteins from DNA damage sites. Following DNA DSBs, it is recruited to the sites of damage by ATM-phosphorylated MDC1 and catalyzes the 'Lys-63'-linked ubiquitination of histones H2A and H2AX, thereby promoting the formation of TP53BP1 and BRCA1 ionizing radiation-induced foci (IRIF). Also controls the recruitment of UIMC1-BRCC3 (RAP80-BRCC36) and PAXIP1/PTIP to DNA damage sites. Also recruited at DNA interstrand cross-links (ICLs) sites and catalyzes 'Lys-63'-linked ubiquitination of histones H2A and H2AX, leading to recruitment of FAAP20/C1orf86 and Fanconi anemia (FA) complex, followed by interstrand cross-link repair. H2A ubiquitination also mediates the ATM-dependent transcriptional silencing at regions flanking DSBs in cis, a mechanism to avoid collision between transcription and repair intermediates. Promotes the formation of 'Lys-63'-linked polyubiquitin chains via interactions with the specific ubiquitin-conjugating UBE2N/UBC13 and ubiquitinates non-histone substrates such as PCNA. Substrates that are polyubiquitinated at 'Lys-63' are usually not targeted for degradation. Also catalyzes the formation of 'Lys-48'-linked polyubiquitin chains via interaction with the ubiquitin-conjugating UBE2L6/UBCH8, leading to degradation of substrate proteins such as CHEK2, JMJD2A/KDM4A and KU80/XRCC5: it is still unclear how the preference toward 'Lys-48'- versus 'Lys-63'-linked ubiquitination is regulated but it could be due to RNF8 ability to interact with specific E2 specific ligases. For instance, interaction with phosphorylated HERC2 promotes the association between RNF8 and UBE2N/UBC13 and favors the specific formation of 'Lys-63'-linked ubiquitin chains. Promotes non-homologous end joining (NHEJ) by promoting the 'Lys-48'-linked ubiquitination and degradation the of KU80/XRCC5. Following DNA damage, mediates the ubiquitination and degradation of JMJD2A/KDM4A in collaboration with RNF168, leading to unmask H4K20me2 mark and promote the recruitment of TP53BP1 at DNA damage sites. In addition to its function in damage signaling, also plays a role in higher-order chromatin structure by mediating extensive chromatin decondensation. Involved in the activation of ATM by promoting histone H2B ubiquitination, which indirectly triggers histone H4 'Lys-16' acetylation (H4K16ac), establishing a chromatin environment that promotes efficient activation of ATM kinase. Required in the testis, where it plays a role in the replacement of histones during spermatogenesis. At uncapped telomeres, promotes the joining of deprotected chromosome ends by inducing H2A ubiquitination and TP53BP1 recruitment, suggesting that it may enhance cancer development by aggraving telomere-induced genome instability in case of telomeric crisis. Promotes the assembly of RAD51 at DNA DSBs in the absence of BRCA1 and TP53BP1 Also involved in class switch recombination in immune system, via its role in regulation of DSBs repair. May be required for proper exit from mitosis after spindle checkpoint activation and may regulate cytokinesis. May play a role in the regulation of RXRA-mediated transcriptional activity. Not involved in RXRA ubiquitination by UBE2E2. Ref.10 Ref.11 Ref.12 Ref.13 Ref.14 Ref.15 Ref.16 Ref.17 Ref.22 Ref.23 Ref.24 Ref.25 Ref.26 Ref.27 Ref.28 Ref.29 Ref.30 Ref.31 Ref.32 Ref.34 Ref.35 Ref.36 Ref.38 Ref.39
Pathway	Protein modification; protein ubiquitination.
Subunit structure	Homodimer. Forms a E2-E3 ubiquitin ligase complex composed of the RNF8 homodimer and a E2 heterodimer of UBE2N and UBE2V2. Interacts with class III E2s, including UBE2E1, UBE2E2, and UBE2E3 and with UBE2N. Interacts with RXRA. Interacts (via FHA domain) with ATM-phosphorylated MDC1. Interacts (via FHA domain) with 'Thr-4827' phosphorylated HERC2 (via C-terminus). Interacts (via FHA domain) with phosphorylated human herpesvirus 1 ICP0 protein; leading to RNF8 degradation by the proteasome. Ref.2 Ref.10 Ref.11 Ref.12 Ref.14 Ref.18 Ref.21 Ref.33 Ref.35 Ref.39
Subcellular location	Nucleus. Midbody. Chromosome › telomere By similarity. Note: Recruited at uncapped telomeres By similarity. Following DNA double-strand breaks, recruited to the sites of damage. During prophase, concomitant with nuclear envelope breakdown, localizes throughout the cell, with a dotted pattern. In telophase, again in the nucleus and also with a discrete dotted pattern in the cytoplasm. In late telophase and during cytokinesis, localizes in the midbody of the tubulin bridge joining the daughter cells. Does not seem to be associated with condensed chromosomes at any time during the cell cycle. Ref.2 Ref.10 Ref.11 Ref.12 Ref.13 Ref.24 Ref.35 Ref.38
Tissue specificity	Ubiquitous. In fetal tissues, highest expression in brain, thymus and liver. In adult tissues, highest levels in brain and testis, lowest levels in peripheral blood cells. Ref.1 Ref.2
Developmental stage	Low levels at the G1-S boundary increase in intensity during S phase and until the end of the G2 phase. Abruptly decreases in late mitosis (at protein level). Barely detectable in anaphase. Ref.15
Domain	The FHA domain specifically recognizes and binds ATM-phosphorylated MDC1 and 'Thr-4827' phosphorylated HERC2. Ref.12
Post-translational modification	Autoubiquitinated through 'Lys-48' and 'Lys-63' of ubiquitin. 'Lys-63' polyubiquitination is mediated by UBE2N. 'Lys-29'-type polyubiquitination is also observed, but it doesn't require its own functional RING-type zinc finger.
Sequence similarities	Belongs to the RNF8 family. Contains 1 FHA domain. Contains 1 RING-type zinc finger.
Caution	According to a well-established model, RNF8 initiate H2A 'Lys-63'-linked ubiquitination leading to recruitment of RNF168 to amplify H2A 'Lys-63'-linked ubiquitination (Ref.22 and Ref.23). However, other data suggest that RNF168 is the priming ubiquitin ligase by mediating monoubiquitination of 'Lys-13' and 'Lys-15' of nucleosomal histone H2A (H2AK13Ub and H2AK15Ub respectively) (Ref.39). These data suggest that RNF168 might be recruited to DSBs sites in a RNF8-dependent manner by binding to non-histone proteins ubiquitinated via 'Lys-63'-linked and initiates monoubiquitination of H2A, which is then amplified by RNF8 (Ref.39). Additional evidences are however required to confirm these data.
Sequence caution	The sequence BAA31621.2 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended. The sequence BAG60572.1 differs from that shown. Reason: Erroneous translation. Wrong choice of CDS. The sequence EAX03945.1 differs from that shown. Reason: Erroneous gene model prediction.

Ontologies

Keywords
Biological process	Cell cycle Cell division DNA damage DNA repair Mitosis Ubl conjugation pathway
Cellular component	Chromosome Nucleus Telomere
Coding sequence diversity	Alternative splicing Polymorphism
Domain	Zinc-finger
Ligand	Metal-binding Zinc
Molecular function	Chromatin regulator Ligase
PTM	Phosphoprotein Ubl conjugation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	cell division Inferred from electronic annotation. Source: UniProtKB-KW double-strand break repair via nonhomologous end joining Inferred from sequence or structural similarity. Source: UniProtKB histone H2A K63-linked ubiquitination Inferred from direct assay Ref.39. Source: UniProtKB histone H2B ubiquitination Inferred from sequence or structural similarity. Source: UniProtKB histone exchange Inferred from sequence or structural similarity. Source: UniProtKB interstrand cross-link repair Traceable author statement Ref.34. Source: UniProtKB isotype switching Inferred from sequence or structural similarity. Source: UniProtKB mitosis Inferred from electronic annotation. Source: UniProtKB-KW negative regulation of translational elongation Inferred from mutant phenotype Ref.27. Source: UniProtKB positive regulation of DNA repair Inferred from direct assay Ref.12Ref.38. Source: UniProtKB protein K48-linked ubiquitination Inferred from direct assay Ref.36Ref.35Ref.31. Source: UniProtKB protein autoubiquitination Inferred from direct assay Ref.35. Source: UniProtKB response to ionizing radiation Inferred from direct assay Ref.12Ref.38. Source: UniProtKB spermatid development Inferred from sequence or structural similarity. Source: UniProtKB ubiquitin-dependent protein catabolic process Inferred from direct assay Ref.35Ref.31. Source: UniProtKB
Cellular_component	chromosome, telomeric region Inferred from sequence or structural similarity. Source: UniProtKB midbody Inferred from electronic annotation. Source: UniProtKB-SubCell nucleus Inferred from direct assay Ref.12Ref.38. Source: UniProtKB site of double-strand break Inferred from direct assay Ref.35. Source: UniProtKB ubiquitin ligase complex Inferred from direct assay Ref.12Ref.38. Source: UniProtKB
Molecular_function	chromatin binding Inferred from direct assay Ref.12Ref.38. Source: UniProtKB histone binding Inferred from direct assay Ref.12Ref.38. Source: UniProtKB protein homodimerization activity Inferred from direct assay Ref.39. Source: UniProtKB ubiquitin-protein ligase activity Inferred from direct assay Ref.12Ref.38Ref.16Ref.36Ref.35Ref.31Ref.39. Source: UniProtKB zinc ion binding Inferred from direct assay Ref.39. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
MDC1	Q14676	11	EBI-373337,EBI-495644

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: O76064-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: O76064-2)

The sequence of this isoform differs from the canonical sequence as follows:
     81-98: SLNGVWLNRARLEPLRVY → SFPSEKAEDFTAAGERFL
     99-485: Missing.

Note: May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. No experimental confirmation available.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 485

485

E3 ubiquitin-protein ligase RNF8

PRO_0000056048

Regions

Domain

38 – 92

55

FHA

Zinc finger

403 – 441

39

RING-type

Compositional bias

276 – 345

70

Gln-rich

Amino acid modifications

Modified residue

157

1

Phosphoserine Ref.19 Ref.20

Natural variations

Alternative sequence

81 – 98

18

SLNGV…PLRVY → SFPSEKAEDFTAAGERFL in isoform 2.

VSP_036671

Alternative sequence

99 – 485

387

Missing in isoform 2.

VSP_037831

Natural variant

162

1

A → T.
Corresponds to variant rs34338974 [ dbSNP | Ensembl ].

VAR_052096

Natural variant

473

1

I → V.
Corresponds to variant rs1139944 [ dbSNP | Ensembl ].

VAR_052097

Experimental info

Mutagenesis

42

1

R → A: Abolishes interaction with ATM-phosphorylated MDC1. Abolishes interaction with human herpesvirus 1 ICP0. Ref.12 Ref.29 Ref.33

Mutagenesis

403

1

C → S: Marked reduction of E2-dependent ubiquitination of histone H2A. Loss of UBE2E2- and UBE2N-binding. Loss of nuclear localization. Ref.2 Ref.10 Ref.11 Ref.12

Mutagenesis

405

1

I → A: Impairs interaction with UBE2L6/UBCH8 and ability to mediate 'Lys-48'-linked ubiquitination E3 ligase activity, while it still catalyzes 'Lys-63'-linked ubiquitination and still interacts with UBE2N/UBC13. Ref.31 Ref.36 Ref.40

Mutagenesis

406

1

C → S: Abolishes ubiquitin-ligase activity. Ref.29

Mutagenesis

443

1

D → R: Does not affect the monomeric structure but abolishes ability to monoubiquitinate H2A in nucleosomes. Ref.39

Sequence conflict

230

1

V → A in BAD96485. Ref.6

Sequence conflict

334

1

K → R in BAD96485. Ref.6

Secondary structure

1

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485

Helix Strand Turn

Details...

Beta strand

16 – 22

7

Beta strand

29 – 32

4

Beta strand

38 – 49

12

Helix

56 – 58

3

Beta strand

64 – 68

5

Beta strand

74 – 78

5

Beta strand

85 – 87

3

Beta strand

105 – 109

5

Beta strand

119 – 128

10

Helix

129 – 132

4

Helix

133 – 135

3

Helix

360 – 399

40

Turn

404 – 406

3

Beta strand

411 – 416

6

Beta strand

421 – 423

3

Helix

424 – 430

7

Turn

438 – 440

3

Beta strand

447 – 449

3

Helix

451 – 461

11

Helix

466 – 479

14

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified November 1, 1998. Version 1. Checksum: 54650B2FFC9948B1	FASTA	485	55,518
	10 20 30 40 50 60 MGEPGFFVTG DRAGGRSWCL RRVGMSAGWL LLEDGCEVTV GRGFGVTYQL VSKICPLMIS 70 80 90 100 110 120 RNHCVLKQNP EGQWTIMDNK SLNGVWLNRA RLEPLRVYSI HQGDYIQLGV PLENKENAEY 130 140 150 160 170 180 EYEVTEEDWE TIYPCLSPKN DQMIEKNKEL RTKRKFSLDE LAGPGAEGPS NLKSKINKVS 190 200 210 220 230 240 CESGQPVKSQ GKGEVASTPS DNLDPKLTAL EPSKTTGAPI YPGFPKVTEV HHEQKASNSS 250 260 270 280 290 300 ASQRSLQMFK VTMSRILRLK IQMQEKHEAV MNVKKQTQKG NSKKVVQMEQ ELQDLQSQLC 310 320 330 340 350 360 AEQAQQQARV EQLEKTFQEE EQHLQGLEIA QGEKDLKQQL AQALQEHWAL MEELNRSKKD 370 380 390 400 410 420 FEAIIQAKNK ELEQTKEEKE KMQAQKEEVL SHMNDVLENE LQCIICSEYF IEAVTLNCAH 430 440 450 460 470 480 SFCSYCINEW MKRKIECPIC RKDIKSKTYS LVLDNCINKM VNNLSSEVKE RRIVLIRERK AKRLF
	Isoform 2 [UniParc]. Checksum: 0E5E5F3D13560D56	FASTA	98	10,846
	10 20 30 40 50 60 MGEPGFFVTG DRAGGRSWCL RRVGMSAGWL LLEDGCEVTV GRGFGVTYQL VSKICPLMIS 70 80 90 RNHCVLKQNP EGQWTIMDNK SFPSEKAEDF TAAGERFL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Isolation, tissue expression, and chromosomal assignment of a novel human gene which encodes a protein with RING finger motif." Seki N., Hattori A., Sugano S., Suzuki Y., Nakagawara A., Ohhira M., Muramatsu M., Hori T., Saito T. J. Hum. Genet. 43:272-274(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1), TISSUE SPECIFICITY. Tissue: Brain.
[2]	"The RING finger protein RNF8 recruits UBC13 for lysine 63-based self polyubiquitylation." Plans V., Scheper J., Soler M., Loukili N., Okano Y., Thomson T.M. J. Cell. Biochem. 97:572-582(2006) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), SUBCELLULAR LOCATION, TISSUE SPECIFICITY, INTERACTION WITH UBE2E2 AND UBE2N, AUTOUBIQUITINATION, MUTAGENESIS OF CYS-403. Tissue: Fetal brain.
[3]	"Prediction of the coding sequences of unidentified human genes. X. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro." Ishikawa K., Nagase T., Suyama M., Miyajima N., Tanaka A., Kotani H., Nomura N., Ohara O. DNA Res. 5:169-176(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Tissue: Brain.
[4]	"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] (ISOFORM 2). Tissue: Kidney.
[5]	"Cloning of human full-length CDSs in BD Creator(TM) system donor vector." Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A. Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
[6]	Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S. Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Tissue: Hepatoma.
[7]	"The DNA sequence and analysis of human chromosome 6." Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R., Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D., Andrews T.D. , Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H., Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J., Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V., Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J., Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E., Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J., French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J., Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C., Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A., Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R., Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A., Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L., Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I., Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y., Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E., Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A., Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W., Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J., Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M., Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I., Rogers J., Beck S. Nature 425:805-811(2003) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[8]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[9]	"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] (ISOFORM 1). Tissue: Muscle.
[10]	"N-terminally extended human ubiquitin-conjugating enzymes (E2s) mediate the ubiquitination of RING-finger proteins, ARA54 and RNF8." Ito K., Adachi S., Iwakami R., Yasuda H., Muto Y., Seki N., Okano Y. Eur. J. Biochem. 268:2725-2732(2001) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH UBE2E1; UBE2E2 AND UBE2E3, MUTAGENESIS OF CYS-403.
[11]	"The RING finger protein, RNF8, interacts with retinoid X receptor alpha and enhances its transcription-stimulating activity." Takano Y., Adachi S., Okuno M., Muto Y., Yoshioka T., Matsushima-Nishiwaki R., Tsurumi H., Ito K., Friedman S.L., Moriwaki H., Kojima S., Okano Y. J. Biol. Chem. 279:18926-18934(2004) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH RXRA, MUTAGENESIS OF CYS-403.
[12]	"RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins." Mailand N., Bekker-Jensen S., Faustrup H., Melander F., Bartek J., Lukas C., Lukas J. Cell 131:887-900(2007) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, INTERACTION WITH MDC1, DOMAIN, MUTAGENESIS OF ARG-42 AND CYS-403.
[13]	"Ubc13/Rnf8 ubiquitin ligases control foci formation of the Rap80/Abraxas/Brca1/Brcc36 complex in response to DNA damage." Wang B., Elledge S.J. Proc. Natl. Acad. Sci. U.S.A. 104:20759-20763(2007) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION.
[14]	"Orchestration of the DNA-damage response by the RNF8 ubiquitin ligase." Kolas N.K., Chapman J.R., Nakada S., Ylanko J., Chahwan R., Sweeney F.D., Panier S., Mendez M., Wildenhain J., Thomson T.M., Pelletier L., Jackson S.P., Durocher D. Science 318:1637-1640(2007) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH MDC1.
[15]	"Regulation of mitotic exit by the RNF8 ubiquitin ligase." Plans V., Guerra-Rebollo M., Thomson T.M. Oncogene 27:1355-1365(2008) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, DEVELOPMENTAL STAGE.
[16]	"PCNA is ubiquitinated by RNF8." Zhang S., Chea J., Meng X., Zhou Y., Lee E.Y.C., Lee M.Y.W.T. Cell Cycle 7:3399-3404(2008) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[17]	"RNF8-dependent and RNF8-independent regulation of 53BP1 in response to DNA damage." Sakasai R., Tibbetts R. J. Biol. Chem. 283:13549-13555(2008) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[18]	"Noncanonical E2 variant-independent function of UBC13 in promoting checkpoint protein assembly." Huen M.S.Y., Huang J., Yuan J., Yamamoto M., Akira S., Ashley C., Xiao W., Chen J. Mol. Cell. Biol. 28:6104-6112(2008) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH UBE2N.
[19]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-157, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[20]	"Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions." Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K. Sci. Signal. 2:RA46-RA46(2009) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-157, MASS SPECTROMETRY. Tissue: Leukemic T-cell.
[21]	"HERC2 coordinates ubiquitin-dependent assembly of DNA repair factors on damaged chromosomes." Bekker-Jensen S., Rendtlew Danielsen J., Fugger K., Gromova I., Nerstedt A., Lukas C., Bartek J., Lukas J., Mailand N. Nat. Cell Biol. 12:80-86(2010) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH HERC2.
[22]	"The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage." Stewart G.S., Panier S., Townsend K., Al-Hakim A.K., Kolas N.K., Miller E.S., Nakada S., Ylanko J., Olivarius S., Mendez M., Oldreive C., Wildenhain J., Tagliaferro A., Pelletier L., Taubenheim N., Durandy A., Byrd P.J., Stankovic T., Taylor A.M.R., Durocher D. Cell 136:420-434(2009) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[23]	"RNF168 binds and amplifies ubiquitin conjugates on damaged chromosomes to allow accumulation of repair proteins." Doil C., Mailand N., Bekker-Jensen S., Menard P., Larsen D.H., Pepperkok R., Ellenberg J., Panier S., Durocher D., Bartek J., Lukas J., Lukas C. Cell 136:435-446(2009) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[24]	"Accumulation of Pax2 transactivation domain interaction protein (PTIP) at sites of DNA breaks via RNF8-dependent pathway is required for cell survival after DNA damage." Gong Z., Cho Y.-W., Kim J.-E., Ge K., Chen J. J. Biol. Chem. 284:7284-7293(2009) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION.
[25]	"Histone ubiquitination associates with BRCA1-dependent DNA damage response." Wu J., Huen M.S.Y., Lu L.-Y., Ye L., Dou Y., Ljungman M., Chen J., Yu X. Mol. Cell. Biol. 29:849-860(2009) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[26]	"The Rap80-BRCC36 de-ubiquitinating enzyme complex antagonizes RNF8-Ubc13-dependent ubiquitination events at DNA double strand breaks." Shao G., Lilli D.R., Patterson-Fortin J., Coleman K.A., Morrissey D.E., Greenberg R.A. Proc. Natl. Acad. Sci. U.S.A. 106:3166-3171(2009) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[27]	"ATM-dependent chromatin changes silence transcription in cis to DNA double-strand breaks." Shanbhag N.M., Rafalska-Metcalf I.U., Balane-Bolivar C., Janicki S.M., Greenberg R.A. Cell 141:970-981(2010) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[28]	"Critical roles of ring finger protein RNF8 in replication stress responses." Sy S.M., Jiang J., Dong S.S., Lok G.T., Wu J., Cai H., Yeung E.S., Huang J., Chen J., Deng Y., Huen M.S. J. Biol. Chem. 286:22355-22361(2011) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[29]	"DNA-damage response and repair activities at uncapped telomeres depend on RNF8." Peuscher M.H., Jacobs J.J. Nat. Cell Biol. 13:1139-1145(2011) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, MUTAGENESIS OF ARG-42 AND CYS-406.
[30]	"RNF8 regulates assembly of RAD51 at DNA double-strand breaks in the absence of BRCA1 and 53BP1." Nakada S., Yonamine R.M., Matsuo K. Cancer Res. 72:4974-4983(2012) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[31]	"RNF8- and RNF168-dependent degradation of KDM4A/JMJD2A triggers 53BP1 recruitment to DNA damage sites." Mallette F.A., Mattiroli F., Cui G., Young L.C., Hendzel M.J., Mer G., Sixma T.K., Richard S. EMBO J. 31:1865-1878(2012) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN UBIQUITINATION OF KDM4A, MUTAGENESIS OF ILE-405.
[32]	"A new non-catalytic role for ubiquitin ligase RNF8 in unfolding higher-order chromatin structure." Luijsterburg M.S., Acs K., Ackermann L., Wiegant W.W., Bekker-Jensen S., Larsen D.H., Khanna K.K., van Attikum H., Mailand N., Dantuma N.P. EMBO J. 31:2511-2527(2012) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[33]	"Viral E3 ubiquitin ligase-mediated degradation of a cellular E3: viral mimicry of a cellular phosphorylation mark targets the RNF8 FHA domain." Chaurushiya M.S., Lilley C.E., Aslanian A., Meisenhelder J., Scott D.C., Landry S., Ticau S., Boutell C., Yates J.R. III, Schulman B.A., Hunter T., Weitzman M.D. Mol. Cell 46:79-90(2012) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH HUMAN HERPESVIRUS 1 ICP0, MUTAGENESIS OF ARG-42.
[34]	"A ubiquitin-binding protein, FAAP20, links RNF8-mediated ubiquitination to the Fanconi anemia DNA repair network." Yan Z., Guo R., Paramasivam M., Shen W., Ling C., Fox D. III, Wang Y., Oostra A.B., Kuehl J., Lee D.Y., Takata M., Hoatlin M.E., Schindler D., Joenje H., de Winter J.P., Li L., Seidman M.M., Wang W. Mol. Cell 47:61-75(2012) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[35]	"The E3 ligase RNF8 regulates KU80 removal and NHEJ repair." Feng L., Chen J. Nat. Struct. Mol. Biol. 19:201-206(2012) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH UBE2N.
[36]	"Differential regulation of RNF8-mediated Lys48- and Lys63-based poly-ubiquitylation." Lok G.T., Sy S.M., Dong S.S., Ching Y.P., Tsao S.W., Thomson T.M., Huen M.S. Nucleic Acids Res. 40:196-205(2012) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, MUTAGENESIS OF ILE-405.
[37]	"Solution structure of the FHA domain of human ubiquitin ligase protein RNF8." RIKEN structural genomics initiative (RSGI) Submitted (NOV-2005) to the PDB data bank Cited for: STRUCTURE BY NMR OF 8-139.
[38]	"RNF8 transduces the DNA-damage signal via histone ubiquitylation and checkpoint protein assembly." Huen M.S.Y., Grant R., Manke I., Minn K., Yu X., Yaffe M.B., Chen J. Cell 131:901-914(2007) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.35 ANGSTROMS) OF 13-146 IN COMPLEX WITH PHOSPHOPEPTIDE, FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION.
[39]	"RNF168 ubiquitinates K13-15 on H2A/H2AX to drive DNA Damage signaling." Mattiroli F., Vissers J.H., van Dijk W.J., Ikpa P., Citterio E., Vermeulen W., Marteijn J.A., Sixma T.K. Cell 150:1182-1195(2012) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 351-483 IN COMPLEX WITH ZINC, SUBUNIT, FUNCTION, MUTAGENESIS OF ASP-443.
[40]	"Molecular insights into the function of RING Finger (RNF)-containing proteins hRNF8 and hRNF168 in Ubc13/Mms2-dependent ubiquitylation." Campbell S.J., Edwards R.A., Leung C.C., Neculai D., Hodge C.D., Dhe-Paganon S., Glover J.N. J. Biol. Chem. 287:23900-23910(2012) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (4.8 ANGSTROMS) OF 345-485 IN COMPLEX WITH UBE2N, MUTAGENESIS OF ILE-405.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AB012770 Genomic DNA. Translation: BAA33557.1.
AF334675 mRNA. Translation: AAQ14887.1.
AB014546 mRNA. Translation: BAA31621.2. Different initiation.
AK298319 mRNA. Translation: BAG60572.1. Sequence problems.
BT007446 mRNA. Translation: AAP36114.1.
AK222765 mRNA. Translation: BAD96485.1.
AL096712 Genomic DNA. Translation: CAB75689.1.
CH471081 Genomic DNA. Translation: EAX03944.1.
CH471081 Genomic DNA. Translation: EAX03945.1. Sequence problems.
BC007517 mRNA. Translation: AAH07517.1.

IPI

IPI00022561.
IPI00923427.

RefSeq

NP_003949.1. NM_003958.3.
NP_898901.1. NM_183078.2.

UniGene

Hs.485278.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2CSW	NMR	-	A	8-139	[»]
2PIE	X-ray	1.35	A	13-146	[»]
4AYC	X-ray	1.90	A/B	351-485	[»]
4EPO	X-ray	4.80	C/G/H/K/L	345-485	[»]

ProteinModelPortal

O76064.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-31265N.

IntAct

O76064. 17 interactions.

MINT

MINT-1459889.

STRING

9606.ENSP00000362578.

PTM databases

PhosphoSite

O76064.

Proteomic databases

PaxDb

O76064.

PRIDE

O76064.

Protocols and materials databases

DNASU

9025.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000229866; ENSP00000229866; ENSG00000112130.
ENST00000373479; ENSP00000362578; ENSG00000112130.
ENST00000394443; ENSP00000377961; ENSG00000112130.
ENST00000469731; ENSP00000418879; ENSG00000112130.

GeneID

9025.

KEGG

hsa:9025.

UCSC

uc003onq.4. human.

Organism-specific databases

CTD

9025.

GeneCards

GC06P037321.

HGNC

HGNC:10071. RNF8.

HPA

HPA050731.

MIM

611685. gene.

neXtProt

NX_O76064.

PharmGKB

PA34445.

HUGE

Search...

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG242257.

HOGENOM

HOG000154169.

HOVERGEN

HBG023954.

KO

K10667.

OMA

EVTEEDW.

OrthoDB

EOG4TF0KP.

PhylomeDB

O76064.

Enzyme and pathway databases

UniPathway

UPA00143.

Gene expression databases

ArrayExpress

O76064.

Bgee

O76064.

CleanEx

HS_RNF8.

Genevestigator

O76064.

GermOnline

ENSG00000112130. Homo sapiens.

Family and domain databases

Gene3D

2.60.200.20. 1 hit.
3.30.40.10. 1 hit.

InterPro

IPR017335. E3_Ub_ligase_RNF8.
IPR000253. FHA_dom.
IPR008984. SMAD_FHA_domain.
IPR001841. Znf_RING.
IPR013083. Znf_RING/FYVE/PHD.
IPR017907. Znf_RING_CS.
[Graphical view]

PANTHER

PTHR15067:SF3. PTHR15067:SF3. 1 hit.

Pfam

PF00498. FHA. 1 hit.
PF13639. zf-RING_2. 1 hit.
[Graphical view]

PIRSF

PIRSF037950. E3_ubiquit_lig_RNF8. 1 hit.

SMART

SM00240. FHA. 1 hit.
SM00184. RING. 1 hit.
[Graphical view]

SUPFAM

SSF49879. SMAD_FHA. 1 hit.

PROSITE

PS50006. FHA_DOMAIN. 1 hit.
PS00518. ZF_RING_1. 1 hit.
PS50089. ZF_RING_2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

EvolutionaryTrace

O76064.

GenomeRNAi

9025.

NextBio

33813.

SOURCE

Search...

Entry information

Entry name

RNF8_HUMAN

Accession

Primary (citable) accession number: O76064
Secondary accession number(s): A6NN24 , A8MYC0, B4DPG0, Q53H16, Q5NKW5

Entry history

Integrated into UniProtKB/Swiss-Prot:	June 6, 2002
Last sequence update:	November 1, 1998
Last modified:	May 1, 2013
This is version 129 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.