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RNF8_RAT
ID   RNF8_RAT                Reviewed;         487 AA.
AC   Q4KLN8;
DT   24-MAR-2009, integrated into UniProtKB/Swiss-Prot.
DT   02-AUG-2005, sequence version 1.
DT   03-AUG-2022, entry version 126.
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   Rattus norvegicus (Rat).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Rattus.
OX   NCBI_TaxID=10116;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Placenta;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
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; BC099079; AAH99079.1; -; mRNA.
DR   RefSeq; NP_001020898.1; NM_001025727.1.
DR   AlphaFoldDB; Q4KLN8; -.
DR   SMR; Q4KLN8; -.
DR   BioGRID; 262979; 10.
DR   IntAct; Q4KLN8; 10.
DR   MINT; Q4KLN8; -.
DR   STRING; 10116.ENSRNOP00000059852; -.
DR   PhosphoSitePlus; Q4KLN8; -.
DR   PaxDb; Q4KLN8; -.
DR   PRIDE; Q4KLN8; -.
DR   Ensembl; ENSRNOT00000065629; ENSRNOP00000059852; ENSRNOG00000047171.
DR   GeneID; 361815; -.
DR   KEGG; rno:361815; -.
DR   UCSC; RGD:1308035; rat.
DR   CTD; 9025; -.
DR   RGD; 1308035; Rnf8.
DR   eggNOG; KOG3872; Eukaryota.
DR   GeneTree; ENSGT00400000022349; -.
DR   HOGENOM; CLU_023453_1_0_1; -.
DR   InParanoid; Q4KLN8; -.
DR   OMA; YCIKQWR; -.
DR   OrthoDB; 1585372at2759; -.
DR   Reactome; R-RNO-5693565; Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks.
DR   Reactome; R-RNO-5693571; Nonhomologous End-Joining (NHEJ).
DR   Reactome; R-RNO-5693607; Processing of DNA double-strand break ends.
DR   Reactome; R-RNO-69473; G2/M DNA damage checkpoint.
DR   UniPathway; UPA00143; -.
DR   PRO; PR:Q4KLN8; -.
DR   Proteomes; UP000002494; Chromosome 20.
DR   Bgee; ENSRNOG00000047171; Expressed in cerebellum and 20 other tissues.
DR   ExpressionAtlas; Q4KLN8; baseline and differential.
DR   Genevisible; Q4KLN8; RN.
DR   GO; GO:0000781; C:chromosome, telomeric region; ISS:UniProtKB.
DR   GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR   GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR   GO; GO:0030496; C:midbody; IEA:UniProtKB-SubCell.
DR   GO; GO:0005654; C:nucleoplasm; IEA:Ensembl.
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:0042802; F:identical protein binding; ISO:RGD.
DR   GO; GO:0042803; F:protein homodimerization activity; ISS:UniProtKB.
DR   GO; GO:0043130; F:ubiquitin binding; IEA:UniProtKB-UniRule.
DR   GO; GO:0061630; F:ubiquitin protein ligase activity; ISO:RGD.
DR   GO; GO:0031625; F:ubiquitin protein ligase binding; ISO:RGD.
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:0051865; P:protein autoubiquitination; ISO:RGD.
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:0016567; P:protein ubiquitination; IBA:GO_Central.
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; IPR018957; Znf_C3HC4_RING-type.
DR   InterPro; IPR001841; Znf_RING.
DR   InterPro; IPR013083; Znf_RING/FYVE/PHD.
DR   InterPro; IPR017907; Znf_RING_CS.
DR   Pfam; PF00498; FHA; 1.
DR   Pfam; PF00097; zf-C3HC4; 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..487
FT                   /note="E3 ubiquitin-protein ligase RNF8"
FT                   /id="PRO_0000367277"
FT   DOMAIN          38..92
FT                   /note="FHA"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_03067"
FT   ZN_FING         405..443
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          135..195
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        135..160
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOD_RES         157
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:O76064"
SQ   SEQUENCE   487 AA;  55615 MW;  7118C1ED670CB95C CRC64;
     MGEPDPLVSG QLAARRSWCL RRLGMDREWL QLEAGSEVTI GRGFSVTYQL ISKVCPLMIS
     RNHCVLKQNP EGQWTIMDNK SLNGVWLNRE RLAPLQGYCI RKGDHIQLGV PLESKEHAEY
     EYEVIEEDRE SLAPCLAPKN DHTTEKHKGL RTKRKFSSDG VESLPAEGPS DLRCPLAKGS
     SKPAEPEKLH GKGEAASQPL GCLCPTLASL EASERTAGPH ACSTLPKVLE LYPKKQKACS
     PSASQSSLEL FKMTMSRMLK LKTQMQEKQI AVLNVKRQAR KGSSKKVVRM EKELRDLQSQ
     LYAEQAQQQA RVEQLEKTFQ EEEQHLQGLE KEQGECDLKQ QLLQALQEHR ALMEELDRSK
     KDFEKIIQAK NKELERTKEE KDKVQAQKEE VLSHMNDVLE NELQCIICSE YFIEAVTLNC
     AHSFCSFCIS EWMKRKVECP ICRKDIESRT NSLVLDNCIS KMVERLSSDV KERRSVLIRE
     RRAKRLL
 
 
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