RNF8_PONAB
ID RNF8_PONAB Reviewed; 486 AA.
AC Q5R4I2;
DT 11-SEP-2007, integrated into UniProtKB/Swiss-Prot.
DT 21-DEC-2004, sequence version 1.
DT 25-MAY-2022, entry version 110.
DE RecName: Full=E3 ubiquitin-protein ligase RNF8 {ECO:0000255|HAMAP-Rule:MF_03067};
DE EC=2.3.2.27 {ECO:0000255|HAMAP-Rule:MF_03067};
DE AltName: Full=RING finger protein 8 {ECO:0000255|HAMAP-Rule:MF_03067};
DE AltName: Full=RING-type E3 ubiquitin transferase RNF8 {ECO:0000255|HAMAP-Rule:MF_03067};
GN Name=RNF8 {ECO:0000255|HAMAP-Rule:MF_03067};
OS Pongo abelii (Sumatran orangutan) (Pongo pygmaeus abelii).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Pongo.
OX NCBI_TaxID=9601;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain cortex;
RG The German cDNA consortium;
RL Submitted (NOV-2004) to the EMBL/GenBank/DDBJ databases.
CC -!- FUNCTION: E3 ubiquitin-protein ligase that plays a key role in DNA
CC damage signaling via 2 distinct roles: by mediating the 'Lys-63'-linked
CC ubiquitination of histones H2A and H2AX and promoting the recruitment
CC of DNA repair proteins at double-strand breaks (DSBs) sites, and by
CC catalyzing 'Lys-48'-linked ubiquitination to remove target proteins
CC from DNA damage sites. Following DNA DSBs, it is recruited to the sites
CC of damage by ATM-phosphorylated MDC1 and catalyzes the 'Lys-63'-linked
CC ubiquitination of histones H2A and H2AX, thereby promoting the
CC formation of TP53BP1 and BRCA1 ionizing radiation-induced foci (IRIF).
CC Also controls the recruitment of UIMC1-BRCC3 (RAP80-BRCC36) and
CC PAXIP1/PTIP to DNA damage sites. Also recruited at DNA interstrand
CC cross-links (ICLs) sites and catalyzes 'Lys-63'-linked ubiquitination
CC of histones H2A and H2AX, leading to recruitment of FAAP20 and Fanconi
CC anemia (FA) complex, followed by interstrand cross-link repair. H2A
CC ubiquitination also mediates the ATM-dependent transcriptional
CC silencing at regions flanking DSBs in cis, a mechanism to avoid
CC collision between transcription and repair intermediates. Promotes the
CC formation of 'Lys-63'-linked polyubiquitin chains via interactions with
CC the specific ubiquitin-conjugating UBE2N/UBC13 and ubiquitinates non-
CC histone substrates such as PCNA. Substrates that are polyubiquitinated
CC at 'Lys-63' are usually not targeted for degradation. Also catalyzes
CC the formation of 'Lys-48'-linked polyubiquitin chains via interaction
CC with the ubiquitin-conjugating UBE2L6/UBCH8, leading to degradation of
CC substrate proteins such as CHEK2, JMJD2A/KDM4A and KU80/XRCC5: it is
CC still unclear how the preference toward 'Lys-48'- versus 'Lys-63'-
CC linked ubiquitination is regulated but it could be due to RNF8 ability
CC to interact with specific E2 specific ligases. For instance,
CC interaction with phosphorylated HERC2 promotes the association between
CC RNF8 and UBE2N/UBC13 and favors the specific formation of 'Lys-63'-
CC linked ubiquitin chains. Promotes non-homologous end joining (NHEJ) by
CC promoting the 'Lys-48'-linked ubiquitination and degradation the of
CC KU80/XRCC5. Following DNA damage, mediates the ubiquitination and
CC degradation of JMJD2A/KDM4A in collaboration with RNF168, leading to
CC unmask H4K20me2 mark and promote the recruitment of TP53BP1 at DNA
CC damage sites (By similarity). Following DNA damage, mediates the
CC ubiquitination and degradation of POLD4/p12, a subunit of DNA
CC polymerase delta. In the absence of POLD4, DNA polymerase delta complex
CC exhibits higher proofreading activity (By similarity). In addition to
CC its function in damage signaling, also plays a role in higher-order
CC chromatin structure by mediating extensive chromatin decondensation.
CC Involved in the activation of ATM by promoting histone H2B
CC ubiquitination, which indirectly triggers histone H4 'Lys-16'
CC acetylation (H4K16ac), establishing a chromatin environment that
CC promotes efficient activation of ATM kinase. Required in the testis,
CC where it plays a role in the replacement of histones during
CC spermatogenesis. At uncapped telomeres, promotes the joining of
CC deprotected chromosome ends by inducing H2A ubiquitination and TP53BP1
CC recruitment, suggesting that it may enhance cancer development by
CC aggravating telomere-induced genome instability in case of telomeric
CC crisis. Promotes the assembly of RAD51 at DNA DSBs in the absence of
CC BRCA1 and TP53BP1 Also involved in class switch recombination in immune
CC system, via its role in regulation of DSBs repair. May be required for
CC proper exit from mitosis after spindle checkpoint activation and may
CC regulate cytokinesis. May play a role in the regulation of RXRA-
CC mediated transcriptional activity. Not involved in RXRA ubiquitination
CC by UBE2E2 (By similarity). {ECO:0000250|UniProtKB:O76064,
CC ECO:0000255|HAMAP-Rule:MF_03067}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine +
CC [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-
CC cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.;
CC EC=2.3.2.27; Evidence={ECO:0000255|HAMAP-Rule:MF_03067};
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC {ECO:0000255|HAMAP-Rule:MF_03067}.
CC -!- SUBUNIT: Homodimer. Forms a E2-E3 ubiquitin ligase complex composed of
CC the RNF8 homodimer and a E2 heterodimer of UBE2N and UBE2V2. Interacts
CC with class III E2s, including UBE2E1, UBE2E2, and UBE2E3 and with
CC UBE2N. Interacts with RXRA. Interacts (via FHA domain) with
CC phosphorylated HERC2 (via C-terminus). Interacts with PIWIL1; leading
CC to sequester RNF8 in the cytoplasm. Interacts with WRAP53/TCAB1.
CC {ECO:0000255|HAMAP-Rule:MF_03067}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000255|HAMAP-Rule:MF_03067}.
CC Cytoplasm {ECO:0000255|HAMAP-Rule:MF_03067}. Midbody
CC {ECO:0000255|HAMAP-Rule:MF_03067}. Chromosome, telomere
CC {ECO:0000255|HAMAP-Rule:MF_03067}. Note=Recruited at uncapped
CC telomeres. Following DNA double-strand breaks, recruited to the sites
CC of damage. During prophase, concomitant with nuclear envelope
CC breakdown, localizes throughout the cell, with a dotted pattern. In
CC telophase, again in the nucleus and also with a discrete dotted pattern
CC in the cytoplasm. In late telophase and during cytokinesis, localizes
CC in the midbody of the tubulin bridge joining the daughter cells. Does
CC not seem to be associated with condensed chromosomes at any time during
CC the cell cycle. During spermatogenesis, sequestered in the cytoplasm by
CC PIWIL1: RNF8 is released following ubiquitination and degradation of
CC PIWIL1. {ECO:0000255|HAMAP-Rule:MF_03067}.
CC -!- DOMAIN: The FHA domain specifically recognizes and binds ATM-
CC phosphorylated MDC1 and phosphorylated HERC2 (By similarity). This
CC domain is also required for proper recruitment to DNA damage sites
CC after UV irradiation, ionizing radiation, or treatment with an
CC alkylating agent (By similarity). {ECO:0000250|UniProtKB:O76064,
CC ECO:0000255|HAMAP-Rule:MF_03067}.
CC -!- PTM: Autoubiquitinated through 'Lys-48' and 'Lys-63' of ubiquitin.
CC 'Lys-63' polyubiquitination is mediated by UBE2N. 'Lys-29'-type
CC polyubiquitination is also observed, but it doesn't require its own
CC functional RING-type zinc finger. {ECO:0000255|HAMAP-Rule:MF_03067}.
CC -!- SIMILARITY: Belongs to the RNF8 family. {ECO:0000255|HAMAP-
CC Rule:MF_03067}.
CC -!- CAUTION: According to a well-established model, RNF8 initiate H2A 'Lys-
CC 63'-linked ubiquitination leading to recruitment of RNF168 to amplify
CC H2A 'Lys-63'-linked ubiquitination. However, other data suggest that
CC RNF168 is the priming ubiquitin ligase by mediating monoubiquitination
CC of 'Lys-13' and 'Lys-15' of nucleosomal histone H2A (H2AK13Ub and
CC H2AK15Ub respectively). These data suggest that RNF168 might be
CC recruited to DSBs sites in a RNF8-dependent manner by binding to non-
CC histone proteins ubiquitinated via 'Lys-63'-linked and initiates
CC monoubiquitination of H2A, which is then amplified by RNF8. Additional
CC evidence is however required to confirm these data. {ECO:0000255|HAMAP-
CC Rule:MF_03067}.
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DR EMBL; CR861266; CAH93334.1; -; mRNA.
DR RefSeq; NP_001126963.1; NM_001133491.1.
DR AlphaFoldDB; Q5R4I2; -.
DR BMRB; Q5R4I2; -.
DR SMR; Q5R4I2; -.
DR STRING; 9601.ENSPPYP00000018524; -.
DR GeneID; 100173982; -.
DR KEGG; pon:100173982; -.
DR CTD; 9025; -.
DR eggNOG; KOG3872; Eukaryota.
DR InParanoid; Q5R4I2; -.
DR OrthoDB; 1585372at2759; -.
DR UniPathway; UPA00143; -.
DR Proteomes; UP000001595; Unplaced.
DR GO; GO:0000781; C:chromosome, telomeric region; ISS:UniProtKB.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0030496; C:midbody; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0035861; C:site of double-strand break; ISS:UniProtKB.
DR GO; GO:0000151; C:ubiquitin ligase complex; ISS:UniProtKB.
DR GO; GO:0003682; F:chromatin binding; ISS:UniProtKB.
DR GO; GO:0042393; F:histone binding; ISS:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; ISS:UniProtKB.
DR GO; GO:0043130; F:ubiquitin binding; IEA:UniProtKB-UniRule.
DR GO; GO:0004842; F:ubiquitin-protein transferase activity; ISS:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; ISS:UniProtKB.
DR GO; GO:0007049; P:cell cycle; IEA:UniProtKB-KW.
DR GO; GO:0051301; P:cell division; IEA:UniProtKB-KW.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; ISS:UniProtKB.
DR GO; GO:0006302; P:double-strand break repair; ISS:UniProtKB.
DR GO; GO:0006303; P:double-strand break repair via nonhomologous end joining; ISS:UniProtKB.
DR GO; GO:0043486; P:histone exchange; ISS:UniProtKB.
DR GO; GO:0070535; P:histone H2A K63-linked ubiquitination; ISS:UniProtKB.
DR GO; GO:0033522; P:histone H2A ubiquitination; ISS:UniProtKB.
DR GO; GO:0033523; P:histone H2B ubiquitination; ISS:UniProtKB.
DR GO; GO:0045190; P:isotype switching; ISS:UniProtKB.
DR GO; GO:0034244; P:negative regulation of transcription elongation from RNA polymerase II promoter; ISS:UniProtKB.
DR GO; GO:0045739; P:positive regulation of DNA repair; ISS:UniProtKB.
DR GO; GO:0070936; P:protein K48-linked ubiquitination; ISS:UniProtKB.
DR GO; GO:0070534; P:protein K63-linked ubiquitination; ISS:UniProtKB.
DR GO; GO:0010212; P:response to ionizing radiation; ISS:UniProtKB.
DR GO; GO:0007286; P:spermatid development; ISS:UniProtKB.
DR GO; GO:0035093; P:spermatogenesis, exchange of chromosomal proteins; ISS:UniProtKB.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; ISS:UniProtKB.
DR CDD; cd00060; FHA; 1.
DR Gene3D; 3.30.40.10; -; 1.
DR HAMAP; MF_03067; RNF8; 1.
DR InterPro; IPR000253; FHA_dom.
DR InterPro; IPR017335; RNF8.
DR InterPro; IPR008984; SMAD_FHA_dom_sf.
DR InterPro; IPR001841; Znf_RING.
DR InterPro; IPR013083; Znf_RING/FYVE/PHD.
DR InterPro; IPR017907; Znf_RING_CS.
DR Pfam; PF00498; FHA; 1.
DR PIRSF; PIRSF037950; E3_ubiquit_lig_RNF8; 1.
DR SMART; SM00240; FHA; 1.
DR SMART; SM00184; RING; 1.
DR SUPFAM; SSF49879; SSF49879; 1.
DR PROSITE; PS50006; FHA_DOMAIN; 1.
DR PROSITE; PS00518; ZF_RING_1; 1.
DR PROSITE; PS50089; ZF_RING_2; 1.
PE 2: Evidence at transcript level;
KW Cell cycle; Cell division; Chromatin regulator; Chromosome; Cytoplasm;
KW DNA damage; DNA repair; Metal-binding; Mitosis; Nucleus; Phosphoprotein;
KW Reference proteome; Telomere; Transferase; Ubl conjugation;
KW Ubl conjugation pathway; Zinc; Zinc-finger.
FT CHAIN 1..486
FT /note="E3 ubiquitin-protein ligase RNF8"
FT /id="PRO_0000301677"
FT DOMAIN 38..92
FT /note="FHA"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03067"
FT ZN_FING 404..442
FT /note="RING-type"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03067"
FT REGION 68..72
FT /note="Required for interaction with PIWIL1"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03067"
FT REGION 180..207
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 180..204
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 157
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O76064"
SQ SEQUENCE 486 AA; 55634 MW; BD59154C95168BD0 CRC64;
MGEPGFFVTG DRAGGRSWCL RRVGMSAGWL LLEDGCEVTV GRGFGVTYQL VSKICPLMIS
RNHCVLKQNP EGQWTIMDNK SLNGVWLNRA RLEPLSVYSI HQGDYIQLGV PLENKENAEY
EYEVTEEDWE TIYPCLSPKN DQVIEKNKEL RTKRKFSLDE LAGPGAEGPS NLKSKINKVS
CESGQSVKSQ GKGEVSSTPS ENLDPKLTVL EPSKKTTGAP IYLGFPKVTE VHHEQTASNS
SASQRGLQMF KVTMSRILRL KIQMQEKHEA VMNVKKQTQK GNSKKIVQME QELLDLQSQL
CAEQAQQQAR VEQLEKTFQE EEQHLQDLEI AQGEEDLRQQ LAQALQEHWA LMEELNRSKK
DFEAIIQAKN KELEQTKEEK EKVQAQKEEV LSHMNDVLEN ELQCIICSEY FIEAVTLNCA
HSFCSYCINE WMKRKIECPI CRKDIKSKTY SLVLDNCINK MVNNLSSEVK ERRIVLIRER
KVKRLF
