C6orf136 (Chromosome 6 Open Reading Frame 136) is a protein in humans (Homo sapiens) encoded by the C6orf136 gene. The gene is conserved in mammals, mollusks, as well some porifera. While the function of the gene is currently unknown, C6orf136 has been shown to be hypermethylated in response to FOXM1 expression in Head Neck Squamous Cell Carcinoma (HNSCC) tissue cells. Additionally, elevated expression of C6orf136 has been associated with improved survival rates in patients with bladder cancer. C6orf136 has three known isoforms.

Gene

Background C6orf136, also known as DADB-129D20.1, MGC15854, LOC221545, and OTTHUMP00000214979. The gene is a poorly characterized protein coding gene in need of further research. The C6orf136 gene can be accessed on NCBI with accession number NM_001109938.3.

Location C6orf136 is located on the short arm of chromosome 6 (6p21.33), starting at base pair (bp) 30,647,133 and ending at bp 30,653,207. This gene spans 6,074 bit/s on the plus (+) strand and contains a total of 6 exons.

Gene Neighborhood Genes in the neighborhood of C6orf136 are the following: ATAT1, PPP1R10, DHX16, PPP1R18, MDC1, MRPS18B, TUBB, and FLOT1.

mRNA C6orf136 has a total of 3 different isoforms. Isoform 1 is the base version of C6orf136 that encodes for the 315 amino acid protein. Isoform 3 uses an alternate in-frame splice site in the 5' coding region when compared to isoform 1, resulting in isoform 3 being longer than isoform 1. Alternatively, isoform 2 lacks an alternate in-frame exon in the 5' coding region when compared to isoform 1, resulting an isoform 2 being shorter than isoform 1

Protein

General Properties

The sequence for the C6orf136 isoform 1 gene per NCBI is as follows: MYQPSRGAARRLGPCLRAYQARPQDQLYPGTLPFPPLWPHSTTTTSPSSPLFWSPLPPRLPTQRLPQVPP 70 LPLPQIQALSSAWVVLPPGKGEEGPGPELHSGCLDGLRSLFEGPPCPYPGAWIPFQVPGTAHPSPATPSG 140 DPSMEEHLSVMYERLRQELPKLFLQSHDYSLYSLDVEFINEILNIRTKGRTWYILSLTLCRFLAWNYFAH 210 LRLEVLQLTRHPENWTLQARWRLVGLPVHLLFLRFYKRDKDEHYRTYDAYSTFYLNSSGLICRHRLDKLM 280 PSHSPPTPVKKLLVGALVALGLSEPEPDLNLCSKP 315 The bolded region in this sequence indicates a domain of unknown function (DUF2358) found in all three isoforms of C6orf136.

The C6orf136 protein has a molecular weight of 35.8 kD and an isoelectric point of 8.99, making the protein slightly basic and physiological pH.

Domains DUF2358 is a domain of unknown function found within the C6orf136 protein from aa149 to aa274. This domain is highly conserved in the C-terminus region and is evolutionarily conserved from plants to humans. Additionally, a proline rich domain was also predicted from aa29 to aa142 of the human C6orf136 protein.

Structure

Secondary Structure The conserved DUF2358 domain of C6orf136 contains an equal mix of alpha helices and beta sheets interspersed in that region. The N-terminus of the protein contained primarily alpha helices, but was poorly conserved across species.

Tertiary Structure The tertiary structure illustrates a primarily alpha helices in the N-terminus of the protein loosely wound up, followed by a densely packed and folded region correlating to the DUF2358 domain with a mix of alpha helices and beta sheets as determined by I-TASSER.

Regulation

Gene Regulation

Promotor C6orf136 has 5 predicted promotor regions. The GXP_6051617 promotor had the largest number of transcripts and CAGE tags. It's located on the plus (+) strand, starts at position 30646644, ends at position 30647460, and is 817 bp in length. It also has 12 total coding transcripts.

+Promotor Regions of C6orf136Promotor IDStart PositionEnd PositionLength# of Coding TranscriptsGXP_6051617 (+)306466443064746081712GXP_2563514 (+)306489063064994510401GXP_6051618 (+)306500543065109310401GXP_6051619 (+)306502663065142311582GXP_3204858 (+)306516113065265010400

Transcription Factor Binding Sites The following table highlights the most likely transcription factors binding to the GXP_6051617 promotor for C6orf136. +Matrix FamilyDetailed Family InformationV$ZF15C2H2 zinc finger transcription factors 15V$NRF1Nuclear respiratory factor 1V$MYBLCellular and viral myb-like transcriptional regulatorsV$CALMCalmodulin-binding transcription factorsV$ZF07C2H2 zinc finger transcription factors 7V$ZF5FZF5 POZ domain zinc fingerV$HANDTwist subfamily of class B bHLH transcription factorsV$KLFSKrueppel like transcription factorsV$SP1FGC-Box factors SP1/GCV$EGRFEGR/nerve growth factor induced protein C & related factorsV$PLAGPleomorphic adenoma geneV$EBOXE-box binding factorsV$RXRFRXR heterodimer binding sitesV$RREBRas-responsive element binding proteinV$NKXHNKX homeodomain factorsV$ETSFHuman and murine ETS1 factorsV$CEBPCcaat/Enhancer Binding Protein

Expression Pattern C6orf136 is expressed highly in the heart, intestine, brain, and kidney tissue. According to AceView, it is well expressed at 1.3x the average gene expression.

Transcription Regulation

Stem Loop Prediction The 3’ UTR sequence had a total of 7 step loops with a single site for potential miRNA binding. In contrast, the 5’ UTR had only 2 stem loops and contained no other notable regions.

miRNA Targeting TargetScan indicated a single has-miRNA-585-3p miRNA binding site in the 3' UTR, shown to be associated with tumor-suppressing properties with respect to gastric cancer.

Protein Regulation

Subcellular Localization C6orf136 is predicted to be localized primarily in the nucleus in Homo sapiens, but is predicted to be primarily expressed in the mitochondria in other species.

Post-Translational Modification The C6orf136 gene has 8 predicted kinase-specific phosphorylation sites at positions 5, 28, 137, 139, 191, 256, 261, and 303, where 4 of the phosphorylation sites are serines, 3 sites are threonines, and 1 is a tryptophan. Additionally, the protein also has a single predicted SUMOylation site at position 247 on a lysine with a p-value of 0.063.

Homology

Paralogs

No paralogs of C6orf136 have been detected in the human genome.

Orthologs Below is a table of selected orthologs of the C6orf136 gene, including closely and distantly related orthologs. C6orf136 has evolved moderately and evenly over time with a rate faster than Cytochrome C but slower than Fibrinogen Alpha. +Selected Orthologs of C6orf136Genus and speciesCommon nameTaxon ClassDate of Divergence (MYA)Accession #Length (AA)% Identity with Human% Similarity with HumanHomo sapiensHumansPrimates0NP_001103408.1315100%100%Pan troglodytesChimpanzeePrimates6.4PNI76372.1315100%100%Mus musculusMouseRodentia89EDL23245.131580%87%Chiroxiphia lanceolataLance-tailed manakinPasserine318XP_032533412.138460%76%Chelonia mydasSea TurtleTestudines318XP_007068287.238663%74%Gopherus evgoodeiGopher tortoiseTestudines318XP_030399707.1 32060%72%Melopsittacus undulatusParakeetPsittaciformes318XP_033929477.128861%76%Geotrypetes seraphiniGaboon caecilianGymnophiona351.7XP_033771275.141656%70%Danio rerioZebrafishCypriniformes433NP_001076315.142349%70%Apostichopus japonicusSea cucumberSynallactida627PIK49576.137641%59%Strongylocentrotus purpuratusSea UrchinEchinoida627XP_030853574.151838%56%Branchiostoma floridaeLanceletLancelet637XP_035683876.146045%64%Aplysia californicaSea hareAplysiidae736XP_005104721.240925%50%Anopheles darlingiMalaria mosquitoDiptera736ETN63757.130336%53%Crassostrea virginicaOysterOstreoida736XP_022320078.135927%44%Ixodes scapularisTicksIxodida736XP_029848376.135235%51%Mytilus coruscushard-shelled musselMytilida736CAC5413351.136333%59%Pomacea canaliculataChanneled applesnailMollusca736XP_025112199.128624%39%Wasmannia auropunctataElectric antHymenoptera736XP_011701036.138736%56%Trichoplax adhaerensTrichoplaxTricoplaciformes747XP_002109420.141534%57%Amphimedon queenslandicaPoriferaPorifera777XP_019852039.130333%7%

Function +Proteins Interacting with C6orf136ProteinFunctionMethodDatabases Present inTotal # of appearancesCSNK2BLocalized to ER and Golgi, and involved with regulating metabolic pathways, signal transduction, transcription, translation, and replication.Y2HiRefIndex; MINT; IMEx; mentha13PLK1Regulates cell cycle, specifically G2/M transition. Loss of PLK1 expression can induce pro-apoptotic pathways. This is being studied as a target for cancer drugs, specifically colon and lung cancers that are dependent on PLK1. (Oncogene). Also possible leukemia involvement.Y2HiRefIndex; MINT; InnateDB-ALL; IMEx; mentha11RBM8AFound predominantly in nucleus, but also in cytoplasm. Is associated with the mRNAs produced after splicing, and is thought to act as a tag to indicate where introns were present, thus coupling pre- and post-mRNA binding events.Y2H; Affinity Chromotography; Anti-Tag CoimmunoprecipitationiRefIndex; InnateDB-All; MatrixDB; IntAct; IMEx; metha6KIF21AKinesin-like protein (motor protein). Could be involved in microtubule dependent transport. Mutation of this gene results in fibrosis of extraocular muscles. Not much else is currently known about this gene.Affinity Chromotography; Anti-Tag CoimmunoprecipitationMatrixDB; IntAct; IMEx; mentha4FBXW7Gene that encodes for many proteins in the F-box protein family. Mutations in this gene are associated with a variety of cancers (cholangiocarcinoma, Endometrial carcinoma, colorectal carcinoma, bladder cancer, gastric carcinoma, lung squamous cell carcinoma, etc.). Thus it's likely that this gene plays a role in the pathogenesis of human cancers.Genetic InterferenceInnateDB-1

References