Written by Dr. Ambika Tewari Edited by Dr. Maria do Carmo Costa
Mutations in Ataxin-3 protein prevent the normal functioning of a DNA repair enzyme leading to an accumulation of errors
Cells are bombarded by thousands of DNA damaging events each day from internal and external sources. Internal sources include routine processes that occur within cells that generate reactive byproducts, while external sources include ultraviolet radiation. This DNA damage can be detrimental to cells. But the coordination of many DNA repair proteins helps to maintain the integrity of the genome. This prevent the accumulation of mutations that can lead to cancer.
DNA repair proteins play very important roles in the nervous system. During development, cells are actively growing and dividing and can incur many errors during these processes. Therefore, it is not surprising that numerous DNA repair proteins are expressed in the mammalian brain to prevent the accumulation of DNA damage. To much DNA damage can produce devastating consequences.
In fact, DNA repair deficiencies usually result in profound nervous system dysfunction in humans. Examples include neurodegeneration, microcephaly and brain tumors. Altered DNA repair signaling has been implicated in neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. This implicates DNA repair proteins in genome maintenance in the nervous system. There are many different types of DNA damage and DNA repair. Each repair process has its own proteins and sequence of events that lead to either repair or cell death.
Ataxin-3 is known for its role in Spinocerebellar ataxia type 3 (SCA3), an autosomal dominant disorder caused by a repeat expansion in the ATXN3 gene. Symptoms are progressive and include prominent ataxia, impaired balance, spasticity and eye abnormalities. These symptoms are primarily a result of cerebellum dysfunction, but brainstem and spinal cord regions also show abnormalities in SCA3 patients. Recent studies have shown that ataxin-3 is part of a complex of proteins that repair single-strand DNA breaks. A crucial member of this complex, polynucleotide kinase 3’-phosphatase (PNKP), is actively involved in not only repairing single-strand but also double-strand breaks. Since the activity of PNKP is dependent on ataxin-3, this group of researchers were eager to investigate whether ataxin-3 also functioned in the repair of double-strand DNA damage.Continue reading “Failure to repair DNA damage may be linked to SCA3”