Noncoding RNA Activated by

DNA Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...

Damage (NORAD) is a long non-coding RNA (

lncRNA Long non-coding RNAs (long ncRNAs, lncRNA) are a type of RNA, generally defined as transcripts more than 200 nucleotides that are not translated into protein. This arbitrary limit distinguishes long ncRNAs from small non-coding RNAs, such as mic ...

) that responds to DNA damage and plays a significant role in preserving stability (keeping it accurate and unchanged) of genetic information (

genome A genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding genes, other functional regions of the genome such as ...

) within cells. Upon DNA damage, the amount of NORAD increases within cells and work to prevent proteins responsible for stabilizing genomes (PUMILIO proteins) such as PUM1 and

PUM2 Pumilio homolog 2 is an RNA-binding protein that in humans is encoded by the ''PUM2'' gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA ...

from reaching their

mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA is ...

targets and destabilizing them. By sequestering the PUMILIO proteins, NORAD allows the involved mRNA (pieces of genetic information derived from DNA that act as protein-coding messengers), to exert their function and maintain many cellular processes. These functions include the repair of the DNA itself, the control of

cell division Cell division is the process by which a parent cell (biology), cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukar ...

, and the proper segregation of

chromosome A chromosome is a package of DNA containing part or all of the genetic material of an organism. In most chromosomes, the very long thin DNA fibers are coated with nucleosome-forming packaging proteins; in eukaryotic cells, the most import ...

s, which are tightly bundled forms of DNA. Lack of enough NORAD can cause

aneuploidy Aneuploidy is the presence of an abnormal number of chromosomes in a cell (biology), cell, for example a human somatic (biology), somatic cell having 45 or 47 chromosomes instead of the usual 46. It does not include a difference of one or more plo ...

as a possible result, which is an improper segregation of chromosomes that can be extremely harmful in proper cell division and in the creation of healthy gametes like

sperm Sperm (: sperm or sperms) is the male reproductive Cell (biology), cell, or gamete, in anisogamous forms of sexual reproduction (forms in which there is a larger, female reproductive cell and a smaller, male one). Animals produce motile sperm ...

and

egg cell The egg cell or ovum (: ova) is the female Reproduction, reproductive cell, or gamete, in most anisogamous organisms (organisms that reproduce sexually with a larger, female gamete and a smaller, male one). The term is used when the female game ...

Relevance in cancer

Cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...

refers to a large number of diseases where irregular cell growth occurs, characterized by cells dividing uncontrollably. It has the ability to spread beyond the place it started to invade multiple parts of the body. Recent studies suggest that NORAD may be involved in the progression of certain cancer cells by increasing the amount of activity in genes that have the potential to cause uncontrollable cell growth (

oncogene An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.

s), and decreasing the amount of genes that protect the genome ( tumor suppressors). This dysregulation was found in cancers such as

pancreatic cancer Pancreatic cancer arises when cell (biology), cells in the pancreas, a glandular organ behind the stomach, begin to multiply out of control and form a Neoplasm, mass. These cancerous cells have the malignant, ability to invade other parts of ...

stomach cancer Stomach cancer, also known as gastric cancer, is a malignant tumor of the stomach. It is a cancer that develops in the Gastric mucosa, lining of the stomach. Most cases of stomach cancers are gastric carcinomas, which can be divided into a numb ...

breast cancer Breast cancer is a cancer that develops from breast tissue. Signs of breast cancer may include a Breast lump, lump in the breast, a change in breast shape, dimpling of the skin, Milk-rejection sign, milk rejection, fluid coming from the nipp ...

and more. NORAD affects processes involved in the transformation of healthy cells into cancer cells including cell death (

apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...

), cell growth and divisions (

cell proliferation Cell proliferation is the process by which ''a cell grows and divides to produce two daughter cells''. Cell proliferation leads to an exponential increase in cell number and is therefore a rapid mechanism of tissue growth. Cell proliferation ...

), the spread of cancer cells to healthy cells (

metastasis Metastasis is a pathogenic agent's spreading from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, ...

), and a cell's ability to gain migratory characteristics ( epithelial-mesenchymal transition (EMT)).

Gastrointestinal cancer

Gastrointestinal cancer Gastrointestinal cancer refers to malignant conditions of the Human gastrointestinal tract, gastrointestinal tract (GI tract) and accessory organs of digestion, including the esophagus, stomach, biliary system, pancreas, small intestine, large in ...

includes all cancers that involve the organs and accessory organs of the digestive system. NORAD levels have been observed to be elevated in various gastrointestinal cancers including pancreatic and

colorectal cancer Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the Colon (anatomy), colon or rectum (parts of the large intestine). Signs and symptoms may include Lower gastrointestinal ...

. Increased NORAD is believed to be in response to the low oxygen levels seen in the environment of these cancer cells. This environment allows cancer cells to become more invasive and resistant to treatment. Research has indicated that NORAD works against

miRNAs Micro ribonucleic acid (microRNA, miRNA, μRNA) are small, single-stranded, non-coding RNA molecules containing 21–23 nucleotides. Found in plants, animals, and even some viruses, miRNAs are involved in RNA silencing and post-trans ...

to spread cancer. Specifically, miRNAs are short

RNA Ribonucleic acid (RNA) is a polymeric molecule that is essential for most biological functions, either by performing the function itself (non-coding RNA) or by forming a template for the production of proteins (messenger RNA). RNA and deoxyrib ...

s that bind to their target mRNAs and lead to their degradation or inability to produce encoded proteins. Some miRNAs work to prevent cancer however, NORAD competes against these miRNAs, allowing cancer to spread more efficiently. In this process, NORAD acts as a

competing endogenous RNA In molecular biology, competing endogenous RNAs (abbreviated ''ceRNAs'') regulate other RNA transcripts by competing for shared microRNAs (miRNAs). Models for ceRNA regulation describe how changes in the expression of one or multiple miRNA targets ...

(ceRNA). For example, in pancreatic cancer, NORAD helps cancer cells gain the ability to migrate by preventing miRNA from inhibiting a protein that drives EMT.

Other relevant conditions

Rheumatoid arthritis

NORAD levels are seen to be elevated in the fluid component of blood (serum) of patients suffering from Rheumatoid arthritis (RA), an autoimmune disorder that causes deformities in the joints. These elevated NORAD levels are positively correlated to other inflammatory markers such as C-reactive protein (CRP), rheumatoid factor (RF), and erythrocyte sedimentation rate (ESR). Ultimately, this would allow the possibility of using NORAD levels to help in the future early diagnosis of RA.

Premature aging

Premature aging symptoms have been attributed to the loss of NORAD as it leads to increased activity of the PUMILIO proteins, resulting in the repression of genes needed for

and

mitochondrial A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used ...

health, the main energy-supplying compartment of cells. This was seen in mice who were missing NORAD through visible aging signs such as hair loss (

alopecia Hair loss, also known as alopecia or baldness, refers to a loss of hair from part of the head or body. Typically at least the head is involved. The severity of hair loss can vary from a small area to the entire body. Inflammation or scarring ...

), grey fur, and abnormal caving-in of the spine (

kyphosis Kyphosis () is an abnormally excessive convex curvature of the Spinal column, spine as it occurs in the Thoracic spine, thoracic and sacrum, sacral regions. Abnormal inward concave ''lordotic'' curving of the Cervical spine, cervical and Lumba ...

) by 12 months old. Other aging markers were seen on a cellular level, such as mitochondrial dysfunction and chromosomal instability.

References

{{reflist RNA Non-coding RNA