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.[1] 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.[2] Additionally, elevated expression of C6orf136 has been associated with improved survival rates in patients with bladder cancer.[3] C6orf136 has three known isoforms.
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.
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.[4]
Genes in the neighborhood of C6orf136 are the following: ATAT1, PPP1R10, DHX16, PPP1R18, MDC1, MRPS18B, TUBB, and FLOT1.
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
The sequence for the C6orf136 isoform 1 gene per NCBI is as follows:[5] MYQPSRGAARRLGPCLRAYQARPQDQLYPGTLPFPPLWPHSTTTTSPSSPLFWSPLPPRLPTQRLPQVPP 70 LPLPQIQALSSAWVVLPPGKGEEGPGPELHSGCLDGLRSLFEGPPCPYPGAWIPFQVPGTAHPSPATPSG 140 DPSMEEHLSVMYERLRQELPKLFLQSHDYSLYSLDVEFINEILNIRTKGRTWYILSLTLCRFLAWNYFAH 210 LRLEVLQLTRHPENWTLQARWRLVGLPVHLLFLRFYKRDKDEHYRTYDAYSTFYLNSSGLICRHRLDKLM 280 PSHSPPTPVKKLLVGALVALGLSEPEPDLNLCSKP 315The 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.
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.[6] Additionally, a proline rich domain was also predicted from aa29 to aa142 of the human C6orf136 protein.[7]
The conserved DUF2358 domain of C6orf136 contains an equal mix of alpha helices and beta sheets interspersed in that region.[8] [9] [10] The N-terminus of the protein contained primarily alpha helices, but was poorly conserved across species.
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.[11] [12] [13]
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.[14]
| GXP_6051617 (+) | 30646644 | 30647460 | 817 | 12 | |
| GXP_2563514 (+) | 30648906 | 30649945 | 1040 | 1 | |
| GXP_6051618 (+) | 30650054 | 30651093 | 1040 | 1 | |
| GXP_6051619 (+) | 30650266 | 30651423 | 1158 | 2 | |
| GXP_3204858 (+) | 30651611 | 30652650 | 1040 | 0 |
The following table highlights the most likely transcription factors binding to the GXP_6051617 promotor for C6orf136.
| V$ZF15 | C2H2 zinc finger transcription factors 15 | |
| V$NRF1 | Nuclear respiratory factor 1 | |
| V$MYBL | Cellular and viral myb-like transcriptional regulators | |
| V$CALM | Calmodulin-binding transcription factors | |
| V$ZF07 | C2H2 zinc finger transcription factors 7 | |
| V$ZF5F | ZF5 POZ domain zinc finger | |
| V$HAND | Twist subfamily of class B bHLH transcription factors | |
| V$KLFS | Krueppel like transcription factors | |
| V$SP1F | GC-Box factors SP1/GC | |
| V$EGRF | EGR/nerve growth factor induced protein C & related factors | |
| V$PLAG | Pleomorphic adenoma gene | |
| V$EBOX | E-box binding factors | |
| V$RXRF | RXR heterodimer binding sites | |
| V$RREB | Ras-responsive element binding protein | |
| V$NKXH | NKX homeodomain factors | |
| V$ETSF | Human and murine ETS1 factors | |
| V$CEBP | Ccaat/Enhancer Binding Protein |
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.[15]
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.[16]
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.[17] [18]
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.[19]
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.[20] Additionally, the protein also has a single predicted SUMOylation site at position 247 on a lysine with a p-value of 0.063.[21]
No paralogs of C6orf136 have been detected in the human genome.
Below is a table of selected orthologs of the C6orf136 gene, including closely and distantly related orthologs.[22] C6orf136 has evolved moderately and evenly over time with a rate faster than Cytochrome C but slower than Fibrinogen Alpha.
| Homo sapiens | Humans | Primates | 0 | NP_001103408.1 | 315 | 100% | 100% | |
| Pan troglodytes | Chimpanzee | Primates | 6.4 | PNI76372.1 | 315 | 100% | 100% | |
| Mus musculus | Mouse | Rodentia | 89 | EDL23245.1 | 315 | 80% | 87% | |
| Chiroxiphia lanceolata | Lance-tailed manakin | Passerine | 318 | XP_032533412.1 | 384 | 60% | 76% | |
| Chelonia mydas | Sea Turtle | Testudines | 318 | XP_007068287.2 | 386 | 63% | 74% | |
| Gopherus evgoodei | Gopher tortoise | Testudines | 318 | XP_030399707.1 | 320 | 60% | 72% | |
| Melopsittacus undulatus | Parakeet | Psittaciformes | 318 | XP_033929477.1 | 288 | 61% | 76% | |
| Geotrypetes seraphini | Gaboon caecilian | Gymnophiona | 351.7 | XP_033771275.1 | 416 | 56% | 70% | |
| Danio rerio | Zebrafish | Cypriniformes | 433 | NP_001076315.1 | 423 | 49% | 70% | |
| Apostichopus japonicus | Sea cucumber | Synallactida | 627 | PIK49576.1 | 376 | 41% | 59% | |
| Strongylocentrotus purpuratus | Sea Urchin | Echinoida | 627 | XP_030853574.1 | 518 | 38% | 56% | |
| Branchiostoma floridae | Lancelet | Lancelet | 637 | XP_035683876.1 | 460 | 45% | 64% | |
| Aplysia californica | Sea hare | Aplysiidae | 736 | XP_005104721.2 | 409 | 25% | 50% | |
| Anopheles darlingi | Malaria mosquito | Diptera | 736 | ETN63757.1 | 303 | 36% | 53% | |
| Crassostrea virginica | Oyster | Ostreoida | 736 | XP_022320078.1 | 359 | 27% | 44% | |
| Ixodes scapularis | Ticks | Ixodida | 736 | XP_029848376.1 | 352 | 35% | 51% | |
| Mytilus coruscus | hard-shelled mussel | Mytilida | 736 | CAC5413351.1 | 363 | 33% | 59% | |
| Pomacea canaliculata | Channeled applesnail | Mollusca | 736 | XP_025112199.1 | 286 | 24% | 39% | |
| Wasmannia auropunctata | Electric ant | Hymenoptera | 736 | XP_011701036.1 | 387 | 36% | 56% | |
| Trichoplax adhaerens | Trichoplax | Tricoplaciformes | 747 | XP_002109420.1 | 415 | 34% | 57% | |
| Amphimedon queenslandica | Porifera | Porifera | 777 | XP_019852039.1 | 303 | 33% | 7% |
| CSNK2B | Localized to ER and Golgi, and involved with regulating metabolic pathways, signal transduction, transcription, translation, and replication.[23] | Y2H | iRefIndex; MINT; IMEx; mentha | 13 | |
| PLK1 | Regulates 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.[24] | Y2H | iRefIndex; MINT; InnateDB-ALL; IMEx; mentha | 11 | |
| RBM8A | Found 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.[25] | Y2H; Affinity Chromotography; Anti-Tag Coimmunoprecipitation | iRefIndex; InnateDB-All; MatrixDB; IntAct; IMEx; metha | 6 | |
| KIF21A | Kinesin-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.[26] | Affinity Chromotography; Anti-Tag Coimmunoprecipitation | MatrixDB; IntAct; IMEx; mentha | 4 | |
| FBXW7 | Gene 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.[27] | Genetic Interference | InnateDB- | 1 |