KHDC3_HUMAN
ID KHDC3_HUMAN Reviewed; 217 AA.
AC Q587J8; B2RNW7;
DT 04-DEC-2007, integrated into UniProtKB/Swiss-Prot.
DT 10-MAY-2005, sequence version 1.
DT 03-AUG-2022, entry version 117.
DE RecName: Full=KH domain-containing protein 3;
DE AltName: Full=ES cell-associated transcript 1 protein {ECO:0000303|PubMed:17913455};
DE AltName: Full=KHDC3-like protein;
GN Name=KHDC3L;
GN Synonyms=C6orf221 {ECO:0000303|PubMed:21885028},
GN ECAT1 {ECO:0000303|PubMed:17913455};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Embryonic stem cell;
RX PubMed=12787504; DOI=10.1016/s0092-8674(03)00393-3;
RA Mitsui K., Tokuzawa Y., Itoh H., Segawa K., Murakami M., Takahashi K.,
RA Maruyama M., Maeda M., Yamanaka S.;
RT "The homeoprotein Nanog is required for maintenance of pluripotency in
RT mouse epiblast and ES cells.";
RL Cell 113:631-642(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Testis;
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).
RN [3]
RP IDENTIFICATION.
RX PubMed=17913455; DOI=10.1016/j.ygeno.2007.06.003;
RA Pierre A., Gautier M., Callebaut I., Bontoux M., Jeanpierre E.,
RA Pontarotti P., Monget P.;
RT "Atypical structure and phylogenomic evolution of the new eutherian
RT oocyte- and embryo-expressed KHDC1/DPPA5/ECAT1/OOEP gene family.";
RL Genomics 90:583-594(2007).
RN [4]
RP TISSUE SPECIFICITY, AND INVOLVEMENT IN HYDM2.
RX PubMed=21885028; DOI=10.1016/j.ajhg.2011.08.002;
RA Parry D.A., Logan C.V., Hayward B.E., Shires M., Landolsi H., Diggle C.,
RA Carr I., Rittore C., Touitou I., Philibert L., Fisher R.A., Fallahian M.,
RA Huntriss J.D., Picton H.M., Malik S., Taylor G.R., Johnson C.A.,
RA Bonthron D.T., Sheridan E.G.;
RT "Mutations causing familial biparental hydatidiform mole implicate c6orf221
RT as a possible regulator of genomic imprinting in the human oocyte.";
RL Am. J. Hum. Genet. 89:451-458(2011).
RN [5]
RP INTERACTION WITH TLE6.
RX PubMed=26537248; DOI=10.1186/s13059-015-0792-0;
RA Alazami A.M., Awad S.M., Coskun S., Al-Hassan S., Hijazi H.,
RA Abdulwahab F.M., Poizat C., Alkuraya F.S.;
RT "TLE6 mutation causes the earliest known human embryonic lethality.";
RL Genome Biol. 16:R240.1-R240.8(2015).
RN [6]
RP IDENTIFICATION IN THE SCMC COMPLEX WITH NLRP5; OOEP AND TLE6 ISOFORM 1,
RP SUBCELLULAR LOCATION, AND DEVELOPMENTAL STAGE.
RX PubMed=25542835; DOI=10.1093/molehr/gau116;
RA Zhu K., Yan L., Zhang X., Lu X., Wang T., Yan J., Liu X., Qiao J., Li L.;
RT "Identification of a human subcortical maternal complex.";
RL Mol. Hum. Reprod. 21:320-329(2015).
RN [7]
RP FUNCTION, INTERACTION WITH PARP1, SUBCELLULAR LOCATION, INDUCTION,
RP PHOSPHORYLATION AT THR-145 AND THR-156, AND MUTAGENESIS OF THR-145;
RP 150-GLU--SER-159; 150-GLU--VAL-172 AND THR-156.
RX PubMed=31609975; DOI=10.1371/journal.pbio.3000468;
RA Zhang W., Chen Z., Zhang D., Zhao B., Liu L., Xie Z., Yao Y., Zheng P.;
RT "KHDC3L mutation causes recurrent pregnancy loss by inducing genomic
RT instability of human early embryonic cells.";
RL PLoS Biol. 17:e3000468-e3000468(2019).
RN [8]
RP VARIANTS HYDM2 LYS-5; 97-GLN AND 201-GLY.
RX PubMed=23963444; DOI=10.1093/molehr/gat056;
RA Andreasen L., Christiansen O.B., Niemann I., Bolund L., Sunde L.;
RT "NLRP7 or KHDC3L genes and the etiology of molar pregnancies and recurrent
RT miscarriage.";
RL Mol. Hum. Reprod. 19:773-781(2013).
CC -!- FUNCTION: As part of the OOEP-KHDC3 scaffold, recruits BLM and TRIM25
CC to DNA replication forks, thereby promoting the ubiquitination of BLM
CC by TRIM25, enhancing BLM retainment at replication forks and therefore
CC promoting stalled replication fork restart (By similarity). Regulates
CC homologous recombination-mediated DNA repair via recruitment of RAD51
CC to sites of DNA double-strand breaks, and sustainment of PARP1
CC activity, which in turn modulates downstream ATM or ATR activation
CC (PubMed:31609975). Activation of ATM or ATR in response to DNA double-
CC strand breaks may be cell-type specific (By similarity). Its role in
CC DNA double-strand break repair is independent of its role in restarting
CC stalled replication forks (By similarity). As a member of the
CC subcortical maternal complex (SCMC), plays an essential role for
CC zygotes to progress beyond the first embryonic cell divisions via
CC regulation of actin dynamics (By similarity). Required for maintenance
CC of euploidy during cleavage-stage embryogenesis (By similarity).
CC Required for the formation of F-actin cytoplasmic lattices in oocytes
CC which in turn are responsible for symmetric division of zygotes via the
CC regulation of mitotic spindle formation and positioning (By
CC similarity). Ensures proper spindle assembly by regulating the
CC localization of AURKA via RHOA signaling and of PLK1 via a RHOA-
CC independent process (By similarity). Required for the localization of
CC MAD2L1 to kinetochores to enable spindle assembly checkpoint function
CC (By similarity). Promotes neural stem cell neurogenesis and neuronal
CC differentiation in the hippocampus (By similarity). May regulate normal
CC development of learning, memory and anxiety (By similarity). Capable of
CC binding RNA (By similarity). {ECO:0000250|UniProtKB:F6SZT2,
CC ECO:0000250|UniProtKB:Q9CWU5, ECO:0000269|PubMed:31609975}.
CC -!- SUBUNIT: Component of the subcortical maternal complex (SCMC), at least
CC composed of NLRP5, KHDC3L, OOEP, and TLE6 isoform 1 (PubMed:25542835).
CC Within the complex, interacts with NLRP5, KHDC3L and TLE6 isoform 1
CC (PubMed:26537248, PubMed:25542835). The SCMC may facilitate
CC translocation of its components between the nuclear and cytoplasmic
CC compartments (PubMed:25542835). Forms a scaffold complex with
CC OOEP/FLOPED, and interacts with BLM and TRIM25 at DNA replication forks
CC (By similarity). Interacts with PARP1; the interaction is increased
CC following the formation of DNA double-strand breaks (PubMed:31609975).
CC Interacts with NUMA1 (By similarity). {ECO:0000250|UniProtKB:Q9CWU5,
CC ECO:0000269|PubMed:25542835, ECO:0000269|PubMed:26537248,
CC ECO:0000269|PubMed:31609975}.
CC -!- INTERACTION:
CC Q587J8; Q9H8W4: PLEKHF2; NbExp=3; IntAct=EBI-22731520, EBI-742388;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cell cortex
CC {ECO:0000269|PubMed:25542835}. Nucleus {ECO:0000269|PubMed:25542835,
CC ECO:0000269|PubMed:31609975}. Mitochondrion
CC {ECO:0000250|UniProtKB:Q9CWU5}. Cytoplasm, cytoskeleton, microtubule
CC organizing center, centrosome {ECO:0000250|UniProtKB:Q9CWU5}.
CC Chromosome {ECO:0000269|PubMed:31609975}. Note=Localized to centrosomes
CC during interphase and mitosis (By similarity). Localizes to sites of
CC DNA double-strand break repair (PubMed:31609975).
CC {ECO:0000250|UniProtKB:Q9CWU5, ECO:0000269|PubMed:31609975}.
CC -!- TISSUE SPECIFICITY: Expression appears to be maximal in germinal
CC vesicle oocytes, it tails off through metaphase II oocytes and is
CC undetectable following the completion of the oocyte to embryo
CC transition. {ECO:0000269|PubMed:21885028}.
CC -!- DEVELOPMENTAL STAGE: Expressed in oocytes of the fetal ovary
CC (PubMed:25542835). Expressed primarily with other SCMC components in
CC the subcortex of oocytes and early embryos (PubMed:25542835).
CC Expression is excluded from cell-cell contact regions after the 2-cell
CC stage (PubMed:25542835). {ECO:0000269|PubMed:25542835}.
CC -!- INDUCTION: Induced by hydroxyurea and etoposide.
CC {ECO:0000269|PubMed:31609975}.
CC -!- DOMAIN: Contains an atypical KH domain with amino acid changes at
CC critical sites, suggesting that it may not bind RNA.
CC -!- DISEASE: Hydatidiform mole, recurrent, 2 (HYDM2) [MIM:614293]: A
CC disorder characterized by excessive trophoblast development that
CC produces a growing mass of tissue inside the uterus at the beginning of
CC a pregnancy. It leads to abnormal pregnancies with no embryo, and
CC cystic degeneration of the chorionic villi.
CC {ECO:0000269|PubMed:21885028, ECO:0000269|PubMed:23963444}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the KHDC1 family. {ECO:0000305}.
CC -!- CAUTION: The role of human KHDC3L in the restart of replication forks
CC is unclear as it has been shown to not be involved in the process
CC (PubMed:31609975). However it has been shown that the KHDC3L ortholog
CC in macaque is required for the process (By similarity).
CC {ECO:0000250|UniProtKB:F6SZT2, ECO:0000269|PubMed:31609975}.
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DR EMBL; AB211062; BAD95489.1; -; mRNA.
DR EMBL; BC132844; AAI32845.1; -; mRNA.
DR EMBL; BC137160; AAI37161.1; -; mRNA.
DR CCDS; CCDS34484.1; -.
DR RefSeq; NP_001017361.1; NM_001017361.2.
DR AlphaFoldDB; Q587J8; -.
DR SMR; Q587J8; -.
DR CORUM; Q587J8; -.
DR IntAct; Q587J8; 1.
DR STRING; 9606.ENSP00000359392; -.
DR iPTMnet; Q587J8; -.
DR PhosphoSitePlus; Q587J8; -.
DR BioMuta; KHDC3L; -.
DR DMDM; 74721670; -.
DR MassIVE; Q587J8; -.
DR PaxDb; Q587J8; -.
DR PeptideAtlas; Q587J8; -.
DR PRIDE; Q587J8; -.
DR Antibodypedia; 49514; 87 antibodies from 17 providers.
DR DNASU; 154288; -.
DR Ensembl; ENST00000370367.4; ENSP00000359392.3; ENSG00000203908.4.
DR GeneID; 154288; -.
DR KEGG; hsa:154288; -.
DR MANE-Select; ENST00000370367.4; ENSP00000359392.3; NM_001017361.3; NP_001017361.1.
DR UCSC; uc003pgt.5; human.
DR CTD; 154288; -.
DR DisGeNET; 154288; -.
DR GeneCards; KHDC3L; -.
DR HGNC; HGNC:33699; KHDC3L.
DR HPA; ENSG00000203908; Tissue enhanced (testis).
DR MalaCards; KHDC3L; -.
DR MIM; 611687; gene.
DR MIM; 614293; phenotype.
DR neXtProt; NX_Q587J8; -.
DR OpenTargets; ENSG00000203908; -.
DR Orphanet; 254688; Complete hydatidiform mole.
DR Orphanet; 254693; Partial hydatidiform mole.
DR PharmGKB; PA162380388; -.
DR VEuPathDB; HostDB:ENSG00000203908; -.
DR eggNOG; ENOG502QQIF; Eukaryota.
DR GeneTree; ENSGT00940000162601; -.
DR HOGENOM; CLU_115458_0_0_1; -.
DR InParanoid; Q587J8; -.
DR OMA; LSKRPYW; -.
DR OrthoDB; 913590at2759; -.
DR PhylomeDB; Q587J8; -.
DR TreeFam; TF338690; -.
DR PathwayCommons; Q587J8; -.
DR SignaLink; Q587J8; -.
DR BioGRID-ORCS; 154288; 7 hits in 1059 CRISPR screens.
DR GenomeRNAi; 154288; -.
DR Pharos; Q587J8; Tbio.
DR PRO; PR:Q587J8; -.
DR Proteomes; UP000005640; Chromosome 6.
DR RNAct; Q587J8; protein.
DR Bgee; ENSG00000203908; Expressed in oocyte and 41 other tissues.
DR Genevisible; Q587J8; HS.
DR GO; GO:0045179; C:apical cortex; IBA:GO_Central.
DR GO; GO:0005938; C:cell cortex; ISS:UniProtKB.
DR GO; GO:0005813; C:centrosome; ISS:UniProtKB.
DR GO; GO:0005694; C:chromosome; IEA:UniProtKB-SubCell.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0032991; C:protein-containing complex; IDA:UniProtKB.
DR GO; GO:0106333; C:subcortical maternal complex; IDA:UniProtKB.
DR GO; GO:0003723; F:RNA binding; IEA:InterPro.
DR GO; GO:0007015; P:actin filament organization; ISS:UniProtKB.
DR GO; GO:0051656; P:establishment of organelle localization; ISS:UniProtKB.
DR GO; GO:0043066; P:negative regulation of apoptotic process; ISS:UniProtKB.
DR GO; GO:1900006; P:positive regulation of dendrite development; ISS:UniProtKB.
DR GO; GO:2000781; P:positive regulation of double-strand break repair; ISS:UniProtKB.
DR GO; GO:1905168; P:positive regulation of double-strand break repair via homologous recombination; IMP:UniProtKB.
DR GO; GO:0040019; P:positive regulation of embryonic development; ISS:UniProtKB.
DR GO; GO:0050769; P:positive regulation of neurogenesis; ISS:UniProtKB.
DR GO; GO:0032880; P:regulation of protein localization; IMP:UniProtKB.
DR GO; GO:0031297; P:replication fork processing; ISS:UniProtKB.
DR CDD; cd12795; FILIA_N_like; 1.
DR Gene3D; 3.30.1370.10; -; 1.
DR InterPro; IPR036612; KH_dom_type_1_sf.
DR InterPro; IPR031952; MOEP19_KH-like.
DR Pfam; PF16005; MOEP19; 1.
DR SUPFAM; SSF54791; SSF54791; 1.
PE 1: Evidence at protein level;
KW Chromosome; Cytoplasm; Cytoskeleton; Mitochondrion; Nucleus;
KW Phosphoprotein; Reference proteome.
FT CHAIN 1..217
FT /note="KH domain-containing protein 3"
FT /id="PRO_0000311967"
FT DOMAIN 40..103
FT /note="KH; atypical"
FT REGION 1..40
FT /note="Involved in RNA binding"
FT /evidence="ECO:0000250|UniProtKB:Q9CWU5"
FT REGION 129..217
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 129..143
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 160..199
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 202..217
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 145
FT /note="Phosphothreonine; by ATM"
FT /evidence="ECO:0000269|PubMed:31609975"
FT MOD_RES 156
FT /note="Phosphothreonine; by ATM"
FT /evidence="ECO:0000269|PubMed:31609975"
FT MOD_RES 182
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9CWU5"
FT VARIANT 5
FT /note="R -> K (in HYDM2; unknown pathological significance;
FT dbSNP:rs144291287)"
FT /evidence="ECO:0000269|PubMed:23963444"
FT /id="VAR_085059"
FT VARIANT 97
FT /note="E -> Q (in HYDM2; unknown pathological significance;
FT dbSNP:rs564533)"
FT /evidence="ECO:0000269|PubMed:23963444"
FT /id="VAR_054052"
FT VARIANT 201
FT /note="A -> G (in HYDM2; unknown pathological significance;
FT dbSNP:rs561930)"
FT /evidence="ECO:0000269|PubMed:23963444"
FT /id="VAR_054053"
FT MUTAGEN 145
FT /note="T->A: Decreases recruitment of RAD51 to DNA double-
FT strand breaks, PARP1 activity and ATM-CHK2 signaling
FT resulting in a decrease in DNA double-strand break repair."
FT /evidence="ECO:0000269|PubMed:31609975"
FT MUTAGEN 150..172
FT /note="Missing: Abolishes DNA double-strand break repair.
FT Reduces the localization of the homologous recombination
FT DNA repair pathway protein RAD51 to sites of DNA double-
FT strand breaks. May exhibit a dominant negative effect on
FT PARP1 activation, homologous recombination repair and ATM-
FT CHK2 signaling. No effect on restart of stalled replication
FT forks, nascent DNA stability, localization to DNA double-
FT strand break repair sites or interaction with PARP1."
FT /evidence="ECO:0000269|PubMed:31609975"
FT MUTAGEN 150..159
FT /note="Missing: Abolishes DNA double-strand break repair.
FT Reduces the localization of the homologous recombination
FT DNA repair pathway protein RAD51 to sites of DNA double-
FT strand breaks. May exhibit a dominant negative effect on
FT PARP1 activation, homologous recombination repair and ATM-
FT CHK2 signaling. No effect on restart of stalled replication
FT forks, nascent DNA stability, localization to DNA double-
FT strand break repair sites or interaction with PARP1."
FT /evidence="ECO:0000269|PubMed:31609975"
FT MUTAGEN 156
FT /note="T->A: Decreases recruitment of RAD51 to DNA double-
FT strand breaks, PARP1 activity and ATM-CHK2 signaling
FT resulting in a decrease in DNA double-strand break repair."
FT /evidence="ECO:0000269|PubMed:31609975"
FT MUTAGEN 156
FT /note="T->D: No effect on recruitment of RAD51 to DNA
FT double-strand breaks, PARP1 activity, ATM-CHK2 signaling or
FT DNA double-strand break repair."
FT /evidence="ECO:0000269|PubMed:31609975"
SQ SEQUENCE 217 AA; 24306 MW; C36BC89949DB8606 CRC64;
MDAPRRFPTL VQLMQPKAMP VEVLGHLPKR FSWFHSEFLK NPKVVRLEVW LVEKIFGRGG
ERIPHVQGMS QILIHVNRLD PNGEAEILVF GRPSYQEDTI KMIMNLADYH RQLQAKGSGK
ALAQDVATQK AETQRSSIEV REAGTQRSVE VREAGTQRSV EVQEVGTQGS PVEVQEAGTQ
QSLQAANKSG TQRSPEAASK AVTQRFREDA RDPVTRL
