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Between ALS and cancer: perhaps a link in a protein

November 12, 2012
Senataxin, a protein involved in two major hereditary neurodegenerative diseases, including a form of ALS, is now back in the spotlight for its novel role as guardian of genome stability, revealing an interesting parallel between tumours and neurodegenerative diseases. The study, conducted jointly in the laboratories at IFOM, the FIRC Institute of Molecular Oncology in Milan, and at the National Research Council’s Institute of Molecular Genetics in Pavia, under the leadership of Giordano Liberi, is published in the current issue of the authoritative scientific journal Cell.
It is mutated in two rare inherited neurodegenerative diseases, a juvenile form of amyotrophic lateral sclerosis (ALS4) and a rare ataxia with eye muscle defects (AOA2). The protein is senataxin, which has led to the discovery of an important new function that places it at the delicate crossroads between the processes of DNA replication and transcription.
"What clearly emerges from our results - explains Giordano Liberi, author of the research - is that senataxin acts like a police officer directing "traffic" during the replication of particularly "busy" DNA regions." Some regions of the DNA, where highly expressed genes are located, are constantly occupied by transcription complexes. "When DNA is duplicated, the replication fork must to pass through these highly transcribed areas and this is where senataxin intervenes - continues Liberi - avoiding the inevitable collision between the fork and the transcription complex. Just like a traffic officer, senataxin gives priority to replication and thereby avoids dangerous fork blockages."
When senataxin is mutated, transcription interferes with replication and abnormal DNA structures that impede the replication fork accumulate in the cell and make the DNA particularly fragile. Thus, this fragility could be responsible for the two neurodegenerative diseases in which senataxin is mutated.
New challenges now await Liberi and his team: which nervous system cells accumulate DNA lesions? what is their role in the development of the disease? and why does the damage caused by mutations in senataxin occur mainly in the brain? These are just some of the many questions raised by the study published today in Cell. Questions that lie at the still mysterious junction between genetic diseases and cancer. First, we must clarify the involvement of senataxin, guardian of genomic stability, in the molecular mechanisms underlying the formation of tumours, where it is well known that DNA integrity is severely compromised.
"The results of this work are an important part of the picture now emerging in the scientific community - comments Marco Foiani, scientific director of IFOM – that often the gears that drive the tumour machine are also the basis of a wide range of diseases that, while manifesting in diverse ways, are similar in terms of defects at the cellular level. Therefore, genomic instability may be the common denominator between cancer and neurodegenerative diseases such as ALS. Once again, in complete contrast to an “autistic approach” and the sectoralisation of scientific research, this study demonstrates the transversal value of basic research that, while working on fundamental biological mechanisms, can arrive at discoveries whose applications open vistas to a variety of seemingly unrelated areas of investigation".
"Research conducted by Liberi - adds Giuseppe Biamonti, Scientific Director of the National Research Council’s Institute of Molecular Genetics in Pavia - is an important confirmation of the collaboration undertaken by our two Institutions to support research into the fundamental mechanisms underlying the physiology of human cells. We expect that this synergy will contribute to clarifying the role of deregulation of these fundamental mechanisms in the onset of diseases such as cancer and neurodegeneration."
The study was carried out thanks to the support of AIRC and Telethon, among others.
Replication and transcription take place continuously on DNA: they are two essential processes without which the cells could not replicate or function. However, each time the DNA is "used" as a template for transcription or replication, its integrity is endangered, even more so when these two processes occur simultaneously.
During DNA transcription the double helix is opened and a specific enzyme synthesizes a strand of RNA. In this phase the nascent transcript forms a hybrid with the template DNA: this structure is transient because the proteins responsible for transporting the RNA intervene quickly and move the transcript outside the nucleus where it can be translated into protein.
When replication occurs in highly transcribed zones, the presence of these DNA/RNA hybrids is also a major obstacle to passage of the replication fork. Senataxin is the key protein able to solve the tangle: displacing the RNA and giving priority to replication so that it can proceed smoothly.
In the absence of senataxin DNA/RNA hybrids slow down replication and the cell reacts by activating molecular DNA damage alarms. In an effort to protect the genetic material, the cell activates a complex repair mechanism that can be even more harmful than the lesions that triggered it. These same abundantly transcribed regions are transformed into the fragile sites in the DNA that are responsible for the genomic instability associated with defects in senataxin.
This discovery could mark a significant step forward both in cancer research, and in the study of the two neurodegenerative diseases in which senataxin is altered. However, the road to a full understanding of their mechanisms is still long. "First, we must determine whether this DNA fragility is the cause of the two diseases - explains Liberi - Then understand which cells in the nervous system are affected by the DNA lesions associated with development of the disease. They could be the neurons, cells that no longer divide and whose DNA damage was presumably accumulated during development of the nervous system, or cells in continuous multiplication, such as the glia that work to support the neurons and that may be prevented from doing so as a result of serious damage to their DNA. There are many experiments to perform, but we now have a better idea of what to look for: we know that in the absence of senataxin, cells are more prone to genomic instability. That is the direction in which we must look."
    last update: 28/10/13