View source for MORT (long non-coding RNA)

{{infobox gene}}

'''''MORT''''' (Mortal Obligate RNA Transcript (also known as ''ZNF667-AS1'')) is a [[long non-coding RNA]] (lncRNA) of the intergenic type ([[long non-coding RNA#Long intergenic non-coding RNAs (lincRNA)|lincRNA]]) that is specific to humans and great apes.<ref name="Vrba_2015">{{cite journal | vauthors = Vrba L, Garbe JC, Stampfer MR, Futscher BW | title = A lincRNA connected to cell mortality and epigenetically-silenced in most common human cancers | journal = Epigenetics | volume = 10 | issue = 11 | pages = 1074–83 | date = 2015 | pmid = 26646903 | pmc = 4844203 | doi = 10.1080/15592294.2015.1106673 }}</ref> The ''MORT'' transcript is produced in all mortal cell types, but is lost in a large fraction of the most common human cancers and therefore might have a [[Tumor suppressor gene|tumor suppressive]] function.

== Genomic location ==
The ''MORT'' gene is located on [[Chromosome 19 (human)|human chromosome 19]], at position 56,989,000-57,007,000 ([[UCSC Genome Browser|hg19]]) inside a cluster of zinc finger genes (ZNF genes). The ''MORT'' gene consists of 2 [[exon]]s, 260 and 1270 bp, respectively, that are separated by a 16 kbp [[intron]]. A large portion of the second ''MORT'' exon is formed by repetitive elements – two LINEs and an LTR element.<ref name="Vrba_2015" />
The ''MORT'' [[Promoter (genetics)|promoter]] is located in a [[CpG site#CpG islands|CpG island]] and is shared with the ''ZNF667'' gene; the two genes residing in a head to head orientation with one another.  Despite the ''MORT'' gene's location inside a cluster of ZNF genes, the ''MORT'' gene is not homologous to any ZNF genes.  While the ''MORT'' gene is in a head to head orientation with ''ZNF667'', ''MORT'' does not overlap the ''ZNF667'' gene, nor does it share any antisense homology to ''ZNF667'', so the officially used symbol ''ZNF667-AS1'' is somewhat misleading.

== Evolution ==
''MORT'' has orthologs only in [[Hominidae|great apes]] – chimpanzees, gorillas and orangutans, and the RNA expression data indicates that the ''MORT'' transcript is present in these species.<ref name="Vrba_2015" /> Thus, from the phylogenetic point view, ''MORT'' is likely a young lincRNA gene that emerged during evolution of great apes. It is possible that the long life span of the great apes needed evolution of additional genes with tumor suppressive activity, and that ''MORT'' is an example of such.

== Silencing in cancer ==
''MORT'' is expressed in all 16 normal human tissues reported in the [[Illumina (company)|Illumina]] body map data,<ref>{{cite web | title = MORT expression in Illumina Body Map Data | url = https://www.ebi.ac.uk/gxa/experiments/E-MTAB-513?accessKey=&serializedFilterFactors=&queryFactorType=ORGANISM_PART&rootContext=&heatmapMatrixSize=50&displayLevels=false&displayGeneDistribution=false&geneQuery=%5B%7B%22value%22%3A%22ZNF667-AS1%22%7D%5D&_queryFactorValues=1&specific=true&_specific=on&cutoff=0.5}}</ref> as well as all ''in vitro'' cultured, finite lifespan, human cell strains that have been analyzed.  In contrast, ''MORT'' gene expression is lost in a large percentage of human cancers and human cancer cell lines.  Using data from human cancers curated in [[The Cancer Genome Atlas|TCGA]], ''MORT'' RNA expression and [[DNA methylation]] state were evaluated in the 10 most common male cancers and the 10 most common female cancers<ref>{{cite web | publisher = American Cancer Society | year = 2015 | title = Cancer Facts & Figures | location = Atlanta | url = http://www.cancer.org/acs/groups/content/@editorial/documents/document/acspc-044552.pdf  }}</ref> (totalling 17 different cancer types based on TCGA classification). Analysis shows that the ''MORT'' gene expression is silenced by DNA hypermethylation of its CpG island promoter in a majority of human tumor samples in 15 of these 17 human cancers.<ref name="Vrba_2015" />

The 15 tumor types where ''MORT'' is frequently silenced are [[acute myeloid leukemia]], [[Bladder cancer|bladder urothelial carcinoma]], [[Breast cancer|breast invasive carcinoma]], [[Colorectal cancer|colon adenocarcinoma]], [[head and neck squamous-cell carcinoma]], [[Kidney cancer|kidney renal clear cell carcinoma]], [[Kidney cancer|kidney renal papillary cell carcinoma]], [[Hepatocellular carcinoma|liver hepatocellular carcinoma]], [[lung adenocarcinoma]], [[Squamous-cell carcinoma of the lung|lung squamous cell carcinoma]], [[Diffuse large B-cell lymphoma|lymphoid neoplasm diffuse large B-cell lymphoma]], [[pancreatic adenocarcinoma]], [[Colorectal cancer|rectum adenocarcinoma]], [[Melanoma|skin cutaneous melanoma]], and [[Uterine cancer|Uterine Corpus Endometrial Carcinoma]].<ref name="Vrba_2015" />

Since cell immortality is an obligate feature of the cancer cell and ''MORT'' was discovered as a target of epigenetic silencing at the boundary where finite lifespan human cells transition from mortal to immortal, ''MORT’s'' epigenetic inactivation may create a cellular state permissive to cell immortalization and suggests a possible tumor suppressive mechanism of ''MORT''’s action.  If this prediction is true, then epigenetic silencing of ''MORT'' should be an early identifiable lesion during human carcinogenesis and predicted to occur in premalignant lesions where cells have acquired pathologic immortality on their route to malignant transformation.  Indeed, recent work has shown that ''MORT'' is epigenetically silenced in both [[Ductal carcinoma in situ|DCIS]], a premalignant lesion of invasive breast cancer, and colonic adenomas, a premalignant lesion of colon adenocarcinoma.<ref name="Vrba_2017">{{cite journal | vauthors = Vrba L, Futscher BW | title = Epigenetic Silencing of MORT Is an Early Event in Cancer and Is Associated with Luminal, Receptor Positive Breast Tumor Subtypes | journal = Journal of Breast Cancer | volume = 20 | issue = 2 | pages = 198–202 | date = June 2017 | pmid = 28690657 | doi = 10.4048/jbc.2017.20.2.198 }} </ref>  Furthermore epigenetic silencing of ''MORT'' is associated with luminal, hormone receptor positive breast cancer, overexpression of the oncogene [[Cyclin D1|''CCND1'']], and ''[[GATA3]]'' mutations, but is negatively correlated with [[TP53|''p53'']] mutations<ref name="Vrba_2017" />.  In summary, aberrant DNA hypermethylation-mediated epigenetic silencing of ''MORT'' occurs early during human [[carcinogenesis]] probably at the time when a mortal cell pathologically transitions to an immortal cell.

== Cellular Function ==
The precise molecular function of ''MORT'' remains enigmatic; however, it is known that ''MORT'' is found preferentially in the cell cytoplasm with differential density centrifugation indicating that ''MORT'' is enriched in the 100,000&nbsp;g fraction, which contains polysomes, microsomes, endoplasmic reticulum, and the plasma membrane.<ref>{{cite book | vauthors = Lodish H, Berk A, Zipursky SL, Matsudaira P, Baltimore D, Darnell J | title = Molecular Cell Biology | edition = 4th | location = New York | publisher = W. H. Freeman | year =  2000 | url = https://www.ncbi.nlm.nih.gov/books/NBK21475/ | isbn = 978-0-7167-3136-8 }}</ref>  Evidence is mounting that ''MORT'' acts as a regulator of protein translation through interactions with RNA binding proteins.

== References ==
{{Reflist}}

[[Category:Genes]]
[[Category:Genes on human chromosome 19]]
[[Category:Non-coding RNA]]
[[Category:Epigenetics]]
[[Category:Cancer epigenetics]]