Question

Incorrectly spliced RNAs often lead to human pathologies. Scientists have examined cancer cells for splice-specific changes and found that many of the changes disrupt tumor-suppressor gene function [Xu and Lee (2003). Nucl. Acids Res. 31:5635- 5643]\(.\) In general, what would be the effects of splicing changes on these RNAs and the function of tumor-suppressor gene function? How might loss of splicing specificity be associated with cancer?

Short answer

Answer: Splicing changes can lead to the generation of aberrant mRNA molecules, affecting the proper translation into functional proteins. In the context of tumor-suppressor genes, these changes could result in the production of non-functional or harmful proteins, failing to control cell growth and promoting genomic instability. This increases the likelihood of cells becoming cancerous, allowing uncontrolled growth and potentially leading to the development of cancer.

Step-by-step solution

1. Understanding RNA splicing

RNA splicing is an essential process during gene expression in eukaryotes. It involves removing the non-coding sequences, or introns, from the pre-mRNA molecule and joining the coding regions, or exons, together. This process generates a mature mRNA molecule, which can then be translated into a protein.

2. Tumor-suppressor genes

Tumor-suppressor genes are protective genes that play a crucial role in controlling cell growth and preventing the formation of tumors. They do this by repairing DNA damage, controlling the cell division cycle, and promoting programmed cell death or apoptosis. When tumor-suppressor genes function properly, they help maintain genomic stability and inhibit the development of cancer.

3. Consequences of splicing changes on RNAs and tumor-suppressor gene function

Splicing changes can lead to the generation of aberrant mRNA molecules with altered coding regions or even non-coding regions, which might affect the proper translation into functional proteins. In the context of tumor-suppressor genes, these splicing changes could lead to the production of non-functional or even harmful proteins that fail to control cell growth and promote genomic instability. This can increase the likelihood of cells becoming cancerous.

4. Association between loss of splicing specificity and cancer

Loss of splicing specificity could result in the production of abnormal mRNA molecules, leading to a disruption in the normal function of tumor-suppressor genes. This disruption could contribute to the development and progression of cancer by allowing cells to evade the natural defense mechanisms that prevent uncontrolled growth. As a result, cells with impaired tumor-suppressor function due to splicing changes can multiply uncontrollably, eventually forming tumors and potentially leading to cancer. In conclusion, splicing changes affecting tumor-suppressor genes can result in the loss of their protective function, promoting increased cellular growth and possibly leading to the development of cancer. Understanding the relationship between RNA splicing and cancer can help scientists identify potential therapeutic targets to prevent or treat cancer.

Key concepts

Tumor-Suppressor Genes

Tumor-suppressor genes are akin to cellular brakes, ensuring that cells do not proliferate unchecked. These genes encode proteins that contribute to repairing DNA damage, regulating the cell division cycle, and activating apoptosis when necessary. When these genes malfunction, usually as a result of mutations, cells can grow uncontrollably, setting the stage for tumor formation.

Incorrectly spliced RNAs often lead to the inactivation or dysfunction of these critical genes. For example, if alternative splicing results in the deletion of a section of the gene that encodes an important domain of the protein, the resulting protein might be unable to perform its role in cell cycle regulation or DNA repair, thereby predisposing the cell to become cancerous.

Gene Expression

Gene expression is the complex process in which genetic instructions are converted into a functional product, typically a protein. This process includes transcription, where RNA is synthesized based on the DNA template, and translation, where the coded message in mRNA is used to assemble proteins. During transcription, RNA splicing plays a pivotal role by removing non-coding regions (introns) from the pre-mRNA transcript and joining the coding segments (exons) together. A failure in proper splicing can have far-reaching consequences for gene expression, possibly leading to the production of dysfunctional proteins and, ultimately, diseases such as cancer.

mRNA Processing

mRNA processing includes several steps that transform the initial RNA transcript (pre-mRNA) into a mature mRNA ready for translation. Aside from splicing, this includes capping at the 5' end and polyadenylation at the 3' end of the mRNA molecule. Each of these modifications is essential for the stability, nuclear export, and translational efficiency of the mRNA. Splicing defects can result in improperly processed mRNA that could code for malfunctioning proteins or get targeted for degradation, hindering the expression of key tumor-suppressor genes.

Genomic Stability

Genomic stability refers to the ability of a cell to maintain the integrity of its genetic information. Tumor-suppressor genes greatly contribute to this by orchestrating repair processes in the face of DNA damage and preventing cells with severe genetic alterations from continuing to divide. Without proper splicing and the correct expression of tumor-suppressor genes, the cell's ability to maintain genomic stability is compromised, enhancing the potential for cancerous transformations.

Apoptosis

Apoptosis, or programmed cell death, is the process through which cells undergo orderly, self-initiated death as a means of controlling cell numbers and eliminating cells that are unnecessary or detrimental to the organism. Several tumor-suppressor genes are involved in the induction and regulation of apoptosis. Aberrant splicing may disrupt the expression of these genes, disabling this vital control mechanism and enabling damaged or unneeded cells to persist and potentially form tumors.

Cell Division Cycle

The cell division cycle encompasses the series of events that take place in a cell leading to its division and replication. Tumor-suppressor genes act as checkpoints in this cycle, ensuring that cells only proceed to divide when they are healthy and their DNA is intact. Alterations in RNA splicing can result in faulty tumor-suppressor genes, causing abnormal cell cycle progression. This may lead to continuous cell division without the necessary safety checks, a hallmark of cancer cells.

Therefore, RNA splicing is integral to regulating the cell division cycle through its effect on gene expression, especially concerning tumor-suppressor genes, whose proper function is critical to preventing cancer.