The genetic information within a cell is stored in deoxyribonucleic acid (DNA), which exists as a double-helix structure composed of two long, complementary strands. To build proteins, the DNA sequence must first be copied into a messenger molecule (mRNA) through a process called transcription. The difference between the two DNA strands lies in their functional role during this initial copying stage.
Defining the Sense and Antisense Strands
The terms “sense” and “antisense” are functional labels describing which strand contains the readable protein code and which is used as the blueprint. These names are not permanent features of a strand but are defined relative to a specific gene being transcribed. A single DNA strand can contain the antisense sequence for one gene and the sense sequence for a different gene located further down the chromosome.
The antisense strand is the one that RNA Polymerase reads to construct the mRNA. It is also known as the template strand or the non-coding strand. Its sequence is complementary to the gene’s sequence, acting like a mold. Transcription uses the sequence of the antisense strand to build the new mRNA molecule one nucleotide at a time.
Conversely, the sense strand is often called the coding strand or the non-template strand. Although RNA Polymerase does not physically read this strand, its sequence is identical to the protein-coding message that will eventually be created. It holds the “sense” because its nucleotide sequence directly corresponds to the triplets (codons) that specify the amino acid sequence of the resulting protein. The only difference between the sense DNA strand and the final mRNA molecule is the substitution of thymine (T) with uracil (U) in the RNA.
The Role of Directionality
The distinction between the two strands is enforced by the inherent directionality of the DNA molecule, defined by the chemical structure of the nucleotide sugar-phosphate backbone. Each strand has a 5’ (five prime) end and a 3’ (three prime) end. The two strands of the DNA double helix are antiparallel, meaning they run in opposite directions; one strand goes from 5′ to 3′, while its partner runs from 3′ to 5′.
This polarity is important because RNA Polymerase, the enzyme responsible for transcription, is a directional machine. The enzyme can only synthesize a new nucleic acid strand by adding nucleotides to the 3’ end of the growing chain. Consequently, RNA Polymerase must read the template strand in the 3’ to 5’ direction to create the new mRNA molecule in the opposite 5’ to 3’ direction.
The specific strand that functions as the antisense template is determined by the location of a region called the promoter, which signals the start of a gene. The promoter acts like a signpost, binding the RNA Polymerase and orienting it in a specific direction. Depending on the gene, the promoter can be positioned to make either of the two physical DNA strands serve as the template for transcription.
How Messenger RNA Confirms the Identity
The resulting messenger RNA (mRNA) molecule confirms the identity of the sense strand. During transcription, RNA Polymerase reads the antisense strand, matching its sequence using the base-pairing rules (A pairs with U, G pairs with C). Because the mRNA is built as a complement to the template, its sequence ends up being an exact mirror image of the antisense strand.
Since the antisense strand is complementary to the sense strand, the mRNA molecule carries the exact same sequence as the original sense strand. For example, if a segment of the sense strand reads 5′-ATGC-3′, the antisense template strand reads 3′-TACG-5′. The RNA Polymerase reads the 3′-TACG-5′ template and synthesizes the mRNA sequence 5′-AUGC-3′.
This resulting mRNA sequence, 5′-AUGC-3′, is an exact match to the sense strand, 5′-ATGC-3′, differing only by the substitution of Uracil for Thymine. This identical sequence is why the non-template strand is designated the “sense” strand; it contains the sequence that makes sense to the ribosome for translating the code into a protein. The mRNA is the portable copy that carries the genetic sense out of the nucleus for protein synthesis.
Antisense as a Therapeutic Tool
The precise nature of the antisense concept is harnessed in medicine through Antisense Oligonucleotides (ASOs). ASOs are short, synthetic strands of nucleic acids designed to be complementary to a specific target mRNA sequence within a cell. They act as a highly specific intervention to regulate gene expression.
When introduced, an ASO binds to its target mRNA molecule via base-pairing, forming a double-stranded hybrid structure. This binding triggers the cell’s natural defense mechanisms, which recognize and degrade the double-stranded RNA molecule. The destruction of the target mRNA prevents it from reaching the ribosome to be translated into a protein, thereby silencing the gene.
ASO technology is used to treat conditions caused by the overexpression or malfunction of a specific protein. By designing an ASO to destroy the problematic mRNA, researchers can reduce the levels of the harmful protein. This approach modulates gene expression without permanently altering the patient’s underlying DNA sequence, offering a highly targeted therapeutic option.