AC   MF_03066;
DC   Protein; auto
TR   HAMAP; MF_03066; -; 1; level=0
XX
Names: RNF168
XX
ID   RN168
case <OC:Mammalia>
DE   RecName: Full=E3 ubiquitin-protein ligase RNF168;
DE            EC=2.3.2.27;
DE   AltName: Full=RING finger protein 168;
DE   AltName: Full=RING-type E3 ubiquitin transferase RNF168;
else
DE   RecName: Full=E3 ubiquitin-protein ligase <gene_name>;
DE            EC=2.3.2.27;
DE   AltName: Full=RING finger protein 168;
DE   AltName: Full=RING-type E3 ubiquitin transferase <gene_name>;
end case
GN   Name=RNF168;
XX
case <OC:Mammalia>
CC   -!- FUNCTION: E3 ubiquitin-protein ligase required for accumulation of
CC       repair proteins to sites of DNA damage. Acts with @gn(UBE2N)/@gn(UBC13)
CC       to amplify the @gn(RNF8)-dependent histone ubiquitination. Recruited to
CC       sites of DNA damage at double-strand breaks (DSBs) by binding to
CC       ubiquitinated histone H2A and H2AX and amplifies the @gn(RNF8)-
CC       dependent H2A ubiquitination, promoting the formation of 'Lys-63'-
CC       linked ubiquitin conjugates. This leads to concentrate ubiquitinated
CC       histones H2A and H2AX at DNA lesions to the threshold required for
CC       recruitment of @gn(TP53BP1) and @gn(BRCA1). Also recruited at DNA
CC       interstrand cross-links (ICLs) sites and promotes accumulation of 'Lys-
CC       63'-linked ubiquitination of histones H2A and H2AX, leading to
CC       recruitment of @gn(FAAP20) and Fanconi anemia (FA) complex, followed by
CC       interstrand cross-link repair. H2A ubiquitination also mediates the
CC       ATM-dependent transcriptional silencing at regions flanking DSBs in
CC       cis, a mechanism to avoid collision between transcription and repair
CC       intermediates. Also involved in class switch recombination in immune
CC       system, via its role in regulation of DSBs repair. Following DNA
CC       damage, promotes the ubiquitination and degradation of
CC       @gn(JMJD2A)/@gn(KDM4A) in collaboration with @gn(RNF8), leading to
CC       unmask H4K20me2 mark and promote the recruitment of @gn(TP53BP1) at DNA
CC       damage sites. Not able to initiate 'Lys-63'-linked ubiquitination in
CC       vitro; possibly due to partial occlusion of the @gn(UBE2N)/@gn(UBC13)-
CC       binding region. Catalyzes monoubiquitination of 'Lys-13' and 'Lys-15'
CC       of nucleosomal histone H2A (H2AK13Ub and H2AK15Ub, respectively).
CC   -!- SUBUNIT: Monomer. Interacts with UBE2N/UBC13.
else
CC   -!- FUNCTION: E3 ubiquitin-protein ligase required for accumulation of
CC       repair proteins to sites of DNA damage. Acts with @gn(UBE2N)/@gn(UBC13)
CC       to amplify the @gn(RNF8)-dependent histone ubiquitination. Recruited to
CC       sites of DNA damage at double-strand breaks (DSBs) by binding to
CC       ubiquitinated histone H2A and ubiquitinates histone H2A and H2AX,
CC       leading to amplify the @gn(RNF8)-dependent H2A ubiquitination and
CC       promoting the formation of 'Lys-63'-linked ubiquitin conjugates. This
CC       leads to concentrate ubiquitinated histones H2A and H2AX at DNA lesions
CC       to the threshold required for recruitment of @gn(TP53BP1) and
CC       @gn(BRCA1). Catalyzes monoubiquitination of 'Lys-13' and 'Lys-15' of
CC       nucleosomal histone H2A (H2AK13Ub and H2AK15Ub, respectively).
CC   -!- SUBUNIT: Monomer.
end case
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;
CC   -!- PATHWAY: Protein modification; protein ubiquitination.
CC   -!- SUBCELLULAR LOCATION: Nucleus. Note=Localizes to double-strand breaks
CC       (DSBs) sites of DNA damage.
CC   -!- DOMAIN: The MIU motif (motif interacting with ubiquitin) mediates the
CC       interaction with both 'Lys-48'- and 'Lys-63'-linked ubiquitin chains.
CC       The UMI motif mediates interaction with ubiquitin with a preference for
CC       'Lys-63'-linked ubiquitin. The specificity for different types of
CC       ubiquitin is mediated by juxtaposition of ubiquitin-binding motifs (MIU
CC       and UMI motifs) with LR motifs (LRMs).
case <OC:Mammalia>
CC   -!- PTM: Sumoylated with @gn(SUMO1) by @gn(PIAS4) in response to double-
CC       strand breaks (DSBs).
CC   -!- PTM: Ubiquitinated.
CC   -!- CAUTION: According to a well-established model, @gn(RNF168) cannot
CC       initiate H2A 'Lys-63'-linked ubiquitination and is recruited following
CC       @gn(RNF8)-dependent histone ubiquitination to amplify H2A 'Lys-63'-
CC       linked ubiquitination. However, other data suggest that @gn(RNF168) is
CC       the priming ubiquitin ligase by mediating monoubiquitination of 'Lys-
CC       13' and 'Lys-15' of nucleosomal histone H2A (H2AK13Ub and H2AK15Ub
CC       respectively). These data suggest that @gn(RNF168) might be recruited
CC       to DSBs sites in a @gn(RNF8)-dependent manner by binding to non-histone
CC       proteins ubiquitinated via 'Lys-63'-linked and initiates
CC       monoubiquitination of H2A, which is then amplified by @gn(RNF8).
CC       Additional evidences are however required to confirm these data.
end case
CC   -!- SIMILARITY: Belongs to the RNF168 family.
XX
DR   PROSITE; PS00518; ZF_RING_1; 1; trigger=no
DR   PROSITE; PS50089; ZF_RING_2; 1; trigger=yes
DR   PROSITE; PS50313; GLU_RICH; 0-unlimited; trigger=strict
XX
KW   Chromatin regulator
KW   DNA damage
KW   DNA repair
KW   Metal-binding
KW   Nucleus
KW   Transferase
case <OC:Mammalia>
KW   Ubl conjugation
end case
KW   Ubl conjugation pathway
KW   Zinc
KW   Zinc-finger
XX
GO   GO:0003682; F:chromatin binding
GO   GO:0042393; F:histone binding
GO   GO:0043130; F:ubiquitin binding
GO   GO:0004842; F:ubiquitin-protein transferase activity
GO   GO:0045739; P:positive regulation of DNA repair
GO   GO:0010212; P:response to ionizing radiation
GO   GO:0006302; P:double-strand break repair
GO   GO:0033522; P:histone H2A ubiquitination
GO   GO:0000151; C:ubiquitin ligase complex
GO   GO:0005634; C:nucleus
XX
FT   From: RN168_HUMAN (Q8IYW5)
FT   MOTIF           110..128
FT                   /note="LR motif 1"
FT   Condition: [ILV]-[SC]-[KQE]-P-G-E-[ILV]-R-[RQK]-E-Y-E-x-[EQ]-[ILV]-x-[RK]-x(2)
FT   MOTIF           143..151
FT                   /note="UMI motif"
FT   Condition: E-[EDQ]-Y-I-[RQ]-[RK]-L-L-A
FT   MOTIF           168..191
FT                   /note="MIU motif 1"
FT   Condition: x-E-[EKQR]-Q-[LM]-[KRLE]-x-D-E-x-L-A-[RW]-x-[LIV]-S-x-[DSNKEQ]-[LMI]-[DN]-x(1,4)
FT   MOTIF           439..462
FT                   /note="MIU motif 2"
FT   Condition: R-[RHYWQ]-[RKQ]-Q-E-[EK]-[QHED]-D-[RH]-x-[LF]-A-L-[QER]-[LI]-Q-[RKE]-[EQ]-x-[DNEK]-[KQR]-[ER]-x(2)
FT   MOTIF           466..477
FT                   /note="LR motif 2"
FT   Condition: R-x-[KN]-G-S-x(3)-Y-x-L-R
XX
Size: 422-577;
Related: None;
Template: Q8IYW5;
Scope:
 Eukaryota; Vertebrata
Fusion:
 Nter: None
 Cter: None
Duplicate: None
Plasmid: None
Comments: None
XX
# Revision 1.5 2019/11/20
//