Alternative Splicing and Cancer

Of late, there has been some discussion in the research community on the role of alternative splicing in aging. Is it a relevant mechanism, and where does it fit in the chain of cause and consequence that leads to age-related disease? In the line of research noted here, the relevance of alternative splicing to cancer is considered - and of course cancer is certainly an age-related condition in the sense that the risk rises considerably with the years.

Alternative splicing refers to the fact that one stretch of DNA, one gene, can code for multiple different proteins. Just like epigenetic mechanisms such as DNA methylation, this is another way in which the balance of proteins produced from the genetic blueprint can change over time, in reaction to changing circumstances. So at first glance, age-related changes to alternative splicing look a lot like cellular reactions to rising levels of molecular damage, and are thus probably a secondary consequence of the causes of aging. Proving that beyond a doubt of course requires the implementation of therapies capable of repairing that damage, of which clearance of senescent cells is the closest to clinical availability.

Cancer, which is one of the leading causes of death worldwide, arises from the disruption of essential mechanisms of the normal cell life cycle, such as replication control, DNA repair and cell death. Thanks to the advances in genome sequencing techniques, biomedical researchers have been able to identify many of the genetic alterations that occur in patients and are common among and between tumor types. But until recently, only mutations in DNA were thought to cause cancer. In a new study, researchers show that alterations in a process known as alternative splicing may also trigger the disease.

Although DNA is the instruction manual for a cell growth, maturation, division, and even death, it's proteins that actually carry out the work. The production of proteins is a highly regulated and complex mechanism: cellular machinery reads the DNA fragment that makes up a gene, transcribes it into RNA and, from the RNA, makes proteins. However, each gene can lead to several RNA molecules through alternative splicing, an essential mechanism for multiple biological processes that can be altered in disease conditions.

Using data for more than 4,000 cancer patients from the Cancer Genome Atlas, a team has analyzed the changes in alternative splicing that occur in each tumor patient and studied how these changes could impact the function of genes. The results of the study show that alternative splicing changes lead to a general loss of functional protein domains, and particularly those domains related to functions that are also affected by genetic mutations in cancer patients. "Thanks to our previous research, we know that tumor type and stage can be predicted by observing alterations in alternative splicing. With this new study, we have discovered that changes in alternative splicing that occur in cancer impact protein functions in a way that is similar to that previously described for genetic mutations." All of these alterations in protein functions would cause changes in cells morphology and function, giving them the characteristics of tumor cells, such as a high proliferative potential or the ability to avoid programmed cell death.


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