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 24-JAN-2024, entry version 124. 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}, ECAT1 GN {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; GLN-97 AND GLY-201. 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; P59047: NLRP5; NbExp=2; IntAct=EBI-22731520, EBI-11071382; CC Q587J8; A6NGQ2: OOEP; NbExp=3; IntAct=EBI-22731520, EBI-18583589; CC Q587J8; Q9H8W4: PLEKHF2; NbExp=3; IntAct=EBI-22731520, EBI-742388; CC Q587J8; Q9H808-1: TLE6; NbExp=2; IntAct=EBI-22731520, EBI-32711753; 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}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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 BioGRID; 127542; 1. DR ComplexPortal; CPX-2210; Subcortical maternal complex. DR CORUM; Q587J8; -. DR IntAct; Q587J8; 5. DR STRING; 9606.ENSP00000359392; -. DR iPTMnet; Q587J8; -. DR PhosphoSitePlus; Q587J8; -. DR BioMuta; KHDC3L; -. DR DMDM; 74721670; -. DR MassIVE; Q587J8; -. DR PaxDb; 9606-ENSP00000359392; -. DR PeptideAtlas; Q587J8; -. DR Antibodypedia; 49514; 100 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 AGR; HGNC:33699; -. DR CTD; 154288; -. DR DisGeNET; 154288; -. DR GeneCards; KHDC3L; -. DR HGNC; HGNC:33699; KHDC3L. DR HPA; ENSG00000203908; Tissue enhanced (brain, 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; 5263669at2759; -. DR PhylomeDB; Q587J8; -. DR TreeFam; TF338690; -. DR PathwayCommons; Q587J8; -. DR SignaLink; Q587J8; -. DR SIGNOR; Q587J8; -. DR BioGRID-ORCS; 154288; 7 hits in 1135 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 42 other cell types or tissues. 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; K Homology domain, type 1; 1. DR InterPro; IPR036612; KH_dom_type_1_sf. DR InterPro; IPR031952; MOEP19_KH-like. DR PANTHER; PTHR19447:SF15; KH DOMAIN-CONTAINING PROTEIN 3; 1. DR PANTHER; PTHR19447; OOCYTE-EXPRESSED PROTEIN HOMOLOG-RELATED; 1. DR Pfam; PF16005; MOEP19; 1. DR SUPFAM; SSF54791; Eukaryotic type KH-domain (KH-domain type I); 1. DR Genevisible; Q587J8; HS. 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; uncertain significance; FT dbSNP:rs144291287)" FT /evidence="ECO:0000269|PubMed:23963444" FT /id="VAR_085059" FT VARIANT 97 FT /note="E -> Q (in HYDM2; uncertain significance; FT dbSNP:rs564533)" FT /evidence="ECO:0000269|PubMed:23963444" FT /id="VAR_054052" FT VARIANT 201 FT /note="A -> G (in HYDM2; uncertain 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 FT double-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 FT double-strand breaks. May exhibit a dominant negative FT effect on PARP1 activation, homologous recombination repair FT and ATM-CHK2 signaling. No effect on restart of stalled FT replication forks, nascent DNA stability, localization to FT DNA double-strand break repair sites or interaction with FT 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 FT double-strand breaks. May exhibit a dominant negative FT effect on PARP1 activation, homologous recombination repair FT and ATM-CHK2 signaling. No effect on restart of stalled FT replication forks, nascent DNA stability, localization to FT DNA double-strand break repair sites or interaction with FT PARP1." FT /evidence="ECO:0000269|PubMed:31609975" FT MUTAGEN 156 FT /note="T->A: Decreases recruitment of RAD51 to DNA FT double-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 //