Initiation is the first step and thus the preparation for translation, transcription, and replication. Together, these stages essentially lead to gene expression. Initiation also plays a role in pathophysiology with respect to diseases such as cancer.
What is initiation?
Initiation is the first step and thus the preparation for translation, transcription, and replication. Together, these stages essentially lead to gene expression. Translation involves the synthesis of proteins within the cells of living organisms by means of copied genetic information. Transcription, in contrast, is the synthesis of RNA using DNA as a template, resulting in RNA. Like translation, transcription is an essential part of gene expression. Within genetics, replication is the production of DNA copies. Each of the above processes consists of several phases. The first phase of both replication, translation, and transcription is initiation. Thus, initiation is the starting process of all components of gene expression. Usually, initiation is preceded by the production of a so-called preinitiation complex. The initiations of transcription, translation and replication differ from each other in the nature and purpose of their process. In addition, the phase of initiation differs with the life form and accordingly proceeds differently in eukaryotes than in prokaryotes.
Function and task
To initiate translation, a preinitiation complex is formed. This complex consists of the so-called 40S subunit of the ribosome and the initiator tRNAMet. It also contains GTP and initiation factors. The combination of these elements recognizes mature mRNA at the 5′ end, can bind it and examine it in a subsequent analysis step from the 5’3′ direction. These processes take place until the investigating complex recognizes a so-called start codon or AUG. After recognition of this codon, the ribosomal 60S subunit binds to it, causing the initiation factors to release. Only then can mRNA translation take place in the sense of translation. In all eukaryotes, the gene-expressive step of transcription also depends on a preinitiation complex consisting of different transcription factors. Factors involved in the complex include TFIIA, TFIID, TFIIB, and TFIIF. The template of DNA is fed to the catalytic center of RNA polymerase to facilitate the formation of an initial phosphodiester bond. Only this substep initiates the actual transcription. In the initiation phase of replication, DNA amplification is again triggered by breaking the DNA double helix. This breaking takes place at a specific point on the DNA and is realized with the aid of helicase. After labeling with primase, a polymerase attaches itself to the broken DNA. At the beginning of replication, helical DNA is present in the cell in a disordered, circular or linear arrangement and is also twisted. In order to be replicated, eukaryotic DNA must first be untwisted, resulting in increasing twisting of DNA double strands. During the initiation of replication, cleavage of the DNA strands also occurs. For the initiation of the replication phase, the so-called replication origin is required, from which the starting point depends. At this origin, hydrogen bonding between bases of the single strands is separated during initiation. Following the opening of the strands, priming takes place. An RNA fragment, also called a primer, is attached to the free single strands by means of RNA polymerase primase. This complex corresponds to the primosome and is used by the DNA polymerase as a “jump start”. Once DNA polymerase has begun synthesis of the second DNA strand, it works its way to termination. Thus, any regulation of replication occurs within the initiation phase.
Diseases and disorders
In pathophysiology, the concept of initiation plays a role primarily in the context of cancer cells. Initiation of malignant processes is essentially due to exposure to deleterious and mutanogenic influences. Genetic mechanisms of carcinogenesis include point mutation, amplification, deletion, and chromosome rearrangement.In this context, the point mutation is a variant of the gene mutation in which there is an exchange, addition or replacement of a specific nucleotide within the DNA. Point mutations can consequently be substitutions, transitions and transversions, insertions or deletions. Thus, point mutation leads to changes in the gene product in protein biosynthesis. Amplification involves a cellular process or molecular genetic procedure to amplify the nucleic acid, which in the case of carcinogenesis leads to carcinogenesis. Deletions, in turn, correspond to a loss of DNA segments, which can correspond to the loss of single bases or larger base sequences in terms of whole chromosome segments. If only single bases are affected, the deletion usually occurs in the context of a point mutation. If a whole chromosome is altered via deletion, the term chromosomal aberration is used. In relation to carcinogenesis, the above processes are being investigated by researchers for their role in the initiation of malignant cells. The goal of these research efforts is to develop different measures for cancer prevention. Thus, in the context of carcinogenesis, initiation represents the first step and, in summary, describes the mutation that a cell undergoes as a result of a carcinogen. Theoretically, this mutation can be eliminated by DNA repair or eliminated by apoptosis (cell death). However, especially in older patients, DNA repair mechanisms are no longer strong enough to eliminate the mutation. Thus, the carcinogenic mutation is irreversible. In carcinogenesis, a gene that controls the cell cycle and cell division is always affected by such a mutation. Carcinogens are genotoxic agents that condition malignant initiation and necessarily cause mutation.
