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FLASH GENE
Symbol RNF8 contributors: mct/ - updated : 20-12-2019
HGNC name ring finger protein 8
HGNC id 10071
Location 6p21.2      Physical location : 37.321.747 - 37.362.513
Synonym name
  • ring finger protein (C3HC4 type) 8
  • C3HC4-type zinc finger protein
  • UBC13/UEV-interacting ring finger protein
  • ring finger protein (C3HC4 type) 8
  • Synonym symbol(s) KIAA0646, FLJ12013
    EC.number 6.3.2.-/ 2.3.2.27
    DNA
    TYPE functioning gene
    STRUCTURE 40.77 kb     8 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status confirmed
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    8 - 5639 - 485 - 2007 18077395
    7 - 5434 - 448 - 2007 18077395
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Nervousbrain    
    Reproductivefemale systemovary  highly
     male systemtestis  highly
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • N-terminal FHA-domain-containing region, to localize to sites of DNA damage
  • C-terminal RING-finger (RF) domain
  • conjugated PhosphoP , MetalloP
    HOMOLOGY
    Homologene
    FAMILY
  • RING finger protein, RNF8 family
  • CATEGORY regulatory , transcription factor , tumor suppressor
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,cytosolic
    intracellular,cytoplasm,cytoskeleton,microtubule,centrosome
    intracellular,nucleus,nucleoplasm
    intracellular,nucleus,chromatin/chromosome,kinetochore
    text
  • localized at kinetochores, centrosomes, and the midbody at M phase
  • basic FUNCTION
  • plays a critical role in the early DNA-damage response
  • recruited by MDC1, through phosphodependent interactions between the RNF8 forkhead-associated domain and motifs in MDC1 that are phosphorylated by the DNA-damage activated protein kinase ataxia telangiectasia mutated (ATM)
  • the DNA-damage response is orchestrated by ATM-dependent phosphorylation of MDC1 and RNF8-mediated ubiquitination
  • facilitates the accumulation of checkpoint mediator proteins BRCA1 and TP53BP1 to the damaged chromatin
  • controls DNA damage-induced nuclear foci formation of PAXIP1, which in turn regulates TP53BP1 localization to the DNA damage sites
  • ubiquitin-dependent DNA-damage signaling cascade involving the E34 ubiquitin ligases RNF8 and RNF168 plays key roles in coordinating cell cycle progression and DNA repair
  • facilitate recruitment of TP53BP1 to sites of DNA damage and the ubiquitination pathway mediated by RNF8 and RNF168 plays an integral part in class switch recombination
  • with others ATM signalling mediator proteins, MDC1, RNF168 and TP53BP1 are also required for heterochromatic DSB repair
  • RNF8 and RNF168 effect the formation of lysine 63-linked polyubiquitin (K63Ub) chains on damaged chromatin, including on histones HIST2H2AC and H2AFX, in an ATM-dependent manner
  • E3 ubiquitin ligases RNF8 and RNF168 may participate in cellular responses upon replication stress
  • promotes cell survival upon replication stress
  • required for timely progression through the CHEK1-dependent G2 checkpoint following replication arrest
  • participate in DNA damage response including ionizing radiation (IR)
  • has functions in S phase and G2/M phase progression and in the checkpoint mechanism
  • CHFR and RNF8 may have overlapping targets and/or functions in mitosis
  • RNF8 and CHFR affect chromatin relaxation and modulate ATM activation and DNA damage response pathways
  • RNF8 and CHFR, function together to activate ATM and maintain genomic stability
  • RNF8 RING-finger domain is essential for TPP1 stability and retention at telomeres
  • RNF8 and RNF168 are essential RING-E3 ubiquitin ligases that catalyze the formation of Lys-63 ubiquitin chains in the DNA damage response
  • RNF8 dimerization is essential for the optimal function of both its forkhead-associated and RING domains
  • tripartite regulation of homologous recombination by RNF8, BRCA1, and TP53BP1
  • histone ubiquitination during the DSB pathway is initiated by RNF168 on HIST2H2AC and H2AFX, whereas RNF8 is inactive toward them
  • RNF8-mediated ubiquitination of NBN contributes to the efficient and stable binding of NBN to DNA double-strand break (DSB) and is important for homologous recombination-mediated DSB repair
  • is involved in targeting of the POLD4 for degradation in response to DNA damage
  • RNF8 and RNF168 operate in different modes with their cognate E2 UBE2N at DSBs
  • RNF8 is less abundant than RNF168, and RNF8 is a rate-limiting determinant of focal repair complex assembly
  • RAD18 and RNF8 operate in the same pathway in the promotion of homologous recombination (HR)
  • RNF8 is required for DNA damage repair in neurons
  • RNF8 induces EMT (epithelial-mesenchymal transition) in the breast cancer cells and promotes breast cancer metastasis
  • RNF8 was shown to monoubiquitinate histones H2A and H2B
  • RNF8 and UBE2N are components of a novel cytoplasmic ubiquitin-signaling network that suppresses synapse formation in the brain
  • RNF8 and SCML2 cooperate to regulate ubiquitination during meiosis, an early step to establish active histone modifications for subsequent gene activation
  • RNF8 plays critical roles in maintaining genomic stability by promoting the repair of DNA double-strand breaks (DSBs) through ubiquitin signaling
  • RNF8 regulated NOTCH1 signaling and cell-fate determination of mammary luminal progenitors
  • RNF8 is a central factor in DNA double strand break (DSB) signal transduction
  • CELLULAR PROCESS cell cycle, checkpoint
    nucleotide, transcription, regulation
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    RNF8-RNF168-BRCA1 cascade emerges as a target for mutations in genome instability disorders
    a component
  • RNF8-C1orf86 ubiquitin cascade is critical for recruiting Fanconi anemia (FA) core complex to interstrand crosslinks and for normal function of the FA network
  • INTERACTION
    DNA binding
    RNA
    small molecule metal binding,
  • Zn2+
  • protein
  • binds to RXR alpha through the N-terminal regions of both proteins (functioning as a regulator of RXR alpha-mediated transcriptional activity through interaction between their respective N-terminal regions)
  • targeted to damaged DNA through an interaction with the double-strand break (DSB)-DDR scaffold protein MDC1, establishing a novel function for MDC1)
  • HERC2-RNF8 interaction requires ionising radiation-inducible phosphorylation of HERC2 at Thr 4827, which in turn binds to the forkhead-associated (FHA) domain of RNF8
  • downregulated in many cancer cells and inversely correlated with PLK1
  • regulates K48- and K63-linked poly-ubiquitylation via differential RING-dependent interactions with its E2s UBE2L6 and UBE2N, respectively
  • RNF8 and RNF168 promote VCP-mediated displacement of L3MBTL1 to unmask TP53BP1 chromatin binding sites
  • RNF8 interacts with UBE2N in a manner that is similar to that of the RING-type E3 ubiquitin ligase TRAF6 and the U-box-type E3 ubiquitin ligase, STUB1
  • C1orf86 preferentially binds the ubiquitin product of RNF8-UBE2N, and this ubiquitin-binding activity and RNF8-UBE2N are both required for recruitment of C1orf86 to interstrand crosslinks
  • RNF8 regulates BRCA1-independent homologous recombination in TP53BP1-depleted cells
  • interaction of the E3 ubiquitin ligase RNF8 with NBN, a key regulator of DNA double-strand break (DSB) repair
  • RNF8 participates in the regulation of POLD4
  • USP44 implicated in negative regulation of the RNF8/RNF168 pathway
  • JMJDC1 bound to RNF8 and MDC1, and demethylated MDC1 at Lys45, thereby promoting MDC1-RNF8 interaction, RNF8-dependent MDC1 ubiquitylation and recruitment of RAP80-BRCA1 to polyubiquitylated MDC1
  • mitotic kinases phosphorylate RNF8 and TP53BP1 to inhibit their recruitment to DSB-flanking chromatin
  • ATM-dependent phosphorylation of BCL10 promotes its interaction with and presentation of UBE2N to RNF8, and RNF8-mediated ubiquitination of BCL10 enhances binding of BCL10 and UBE2N to RNF168
  • interacting with TP53BP1 whose ensuing degradation is regulated by RNF8 and RNF168
  • RNF8/RNF168 ubiquitylates gammaH2AX
  • BRCA1 (FANCS), MDC1, and RNF8 are required for BRCA2 (FANCD1) and SLX4 (FANCP) accumulation on the sex chromosomes during meiosis
  • RNF8 is a binding partner of dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2)
  • role of RNF8-mediated histone H3 polyubiquitylation in the regulation of histone H3 stability and chromatin modification, paving the way to gene expression regulation and tumorigenesis
  • HUWE1 primes histone H1 with ubiquitin to allow ubiquitin chain elongation by RNF8, thereby stimulating the RNF8-RNF168 mediated DNA damage response (DDR)
  • L3MBTL2 is recruited by MDC1 and subsequently ubiquitylated by RNF8
  • L3MBTL2 interacted with the histone ubiquitin ligase RNF8
  • L3MBTL2 is the substrate of RNF8
  • VCP-ATXN3 complex is the essential machinery for regulation of RNF8 homeostasis under both physiological and genotoxic conditions
  • cell & other
    REGULATION
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Susceptibility to autism spectrum disorder
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancerreproductivebreast
    could be used as a potential therapeutic target for the prevention and treatment of breast cancer
    ANIMAL & CELL MODELS
  • Rnf8-deficient mice are viable but have multiple phenotypes including a growth retardation phenotype, increased sensitivity to IR, and impaired spermatogenesis
  • RNF8(-/-) mice exhibit neuronal degeneration and reactive astrocytosis
  • loss of Rnf8 or Rad6b can lead to sterility in male mice