Abstract
More than fifteen genetic diseases, including Huntington’s disease, myotonic dystrophy 1, fragile X syndrome and Friedreich ataxia, are caused by the aberrant expansion of a trinucleotide repeat. The mutation is unstable and further expands in specific cells or tissues with time, which can accelerate disease progression. DNA damage and base excision repair (BER) are involved in repeat instability and might contribute to the tissue selectivity of the process. In this review, we will discuss the mechanisms of trinucleotide repeat instability, focusing more specifically on the role of BER.
Highlights
Programme of Translational Medicine and Neurogenetics, Institute of Genetics and Molecular and Cellular Biology (IGBMC), UMR 7104-Centre National de la Recherche Scientifique (CNRS)/INSERM/Uds, 1 rue Laurent Fries, 67404 Illkirch, Tel.: +33-3-88-65-34-06; Fax: +33-3-88-65-32-46
In LP-base excision repair (BER), the flap endonuclease 1 (Fen1) removes the 5'-flap structure generated during the multi-nucleotide synthesis step mediated by polymerase β (Polβ) or a replicative DNA polymerase prior to ligation by DNA ligase I (Lig1) [41,42]
Many genetic diseases are caused by dynamic mutations, including trinucleotide repeat expansion diseases
Summary
Trinucleotide repeat (TNR) disorders define a group of more than fifteen neurodegenerative, neurological and neuromuscular diseases [1,2]. These genetic diseases result from the aberrant expansion of TNRs within specific genes. TNR expansions are dynamic mutations, which are ongoing across generations and within tissues, due to germline and somatic instability, respectively [3]. Expansion events tend to be more frequent than contraction events, leading to the progressive increase of the repeat tract with age. It is noteworthy that in most CAG/CTG diseases, repeat instability is generally elevated in brain tissues, with the exception of the cerebellum, which presents limited repeat instability [2]. Somatic CAG instability is usually great in the central nervous system and, in neurons, indicative of the implication of replication-independent mechanisms [6]
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