# C6orf136

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:
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 C6orf136 :
| Promotor ID | Start Position | End Position | Length | # of Coding Transcripts |
| 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 |

#### Transcription Factor Binding Sites

The following table highlights the most likely transcription factors binding to the GXP_6051617 promotor for C6orf136.
| Matrix Family | Detailed Family Information |
| 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 |

#### 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 C6orf136 :
| Genus and Species | Common Name | Taxon Class | Date of Divergence (MYA) | Accession # | Length (AA) | % Identity with Human | % Similarity with Human |
| 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% |

## Function

Proteins Interacting with C6orf136 :
| Protein | Function | Method | Databases Present in | Total # of appearances |
| CSNK2B | Localized to ER and Golgi, and involved with regulating metabolic pathways, signal transduction, transcription, translation, and replication. | 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. | 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. | 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. | 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. | Genetic Interference | InnateDB- | 1 |