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Several human neurological and neuromuscular diseases are caused by the expansion of repetitive DNA tracts. Understanding the DNA metabolic processes responsible for the expansion (or lengthening) and contraction (or shortening) of DNA repeats might open new therapeutic avenues for the treatment of these diseases.
An unstable genome is a hallmark of many cancer cells. Telomeres prevent the ends of linear chromosomes from being recognized as damaged DNA, thus protecting them from DNA repair mechanisms and inhibiting the breakage–fusion–bridge cycles that cause genome instability.
Genomic architecture can be markedly affected during meiosis by non-allelic homologous recombination (NAHR), which generates chromosomal rearrangements that can lead to genome instability. Studies in yeast have provided insights into the mechanisms of NAHR and the strategies used to restrain it.
Homologous recombination maintains genome stability in mammalian mitotic cells through precise repair of DNA double-strand breaks and other lesions that occur during normal cellular metabolism and through exogenous insults. Deficiencies in genes that encode proteins involved in homologous recombination are associated with developmental abnormalities and tumorigenesis.
During DNA replication, secondary structures, highly transcribed DNA sequences and damaged DNA stall replication forks, which then require checkpoint factors and specialized enzymes for their stabilization and subsequent advance. The mechanisms promoting replication fork integrity and genome stability in eukaryotic cells are becoming clear.
Genomic instability in hereditary cancers results from mutations in DNA repair genes, as predicted by the mutator hypothesis. However, high-throughput sequencing studies show that mutations in DNA repair genes are infrequent in non-hereditary cancers, leaving open the possibility that genomic instability in these cancers may be related to oncogene-induced DNA damage.
