Mystery of Expansion: DNA Metabolism and Unstable Repeats

Abstract

The mammalian genome mostly contains repeated sequences. Some of these repeats are in the regulatory elements of genes, and their instability, particularly the propensity to change the repeat unit number, is responsible for 36 well-known neurodegenerative human disorders. The mechanism of repeat expansion has been an unsolved question for more than 20 years. There are a few hypotheses describing models of mutation development. Every hypothesis is based on assumptions about unusual secondary structures that violate DNA metabolism processes in the cell. Some models are based on replication errors, and other models are based on mismatch repair or base excision repair errors. Additionally, it has been shown that epigenetic regulation of gene expression can influence the probability and frequency of expansion. In this review, we consider the molecular bases of repeat expansion disorders and discuss possible mechanisms of repeat expansion during cell metabolism.