Precarious maintenance of simple DNA repeats in eukaryotes

Abstract

In this review, we discuss how two evolutionarily conserved pathways at the interface of DNA replication and repair, template switching and break-induced replication, lead to the deleterious large-scale expansion of trinucleotide DNA repeats that cause numerous hereditary diseases. We highlight that these pathways, which originated in prokaryotes, may be subsequently hijacked to maintain long DNA microsatellites in eukaryotes. We suggest that the negative mutagenic outcomes of these pathways, exemplified by repeat expansion diseases, are likely outweighed by their positive role in maintaining functional repetitive regions of the genome such as telomeres and centromeres.

Nanopore sequencing of complex genomic rearrangements in yeast reveals mechanisms of repeat-mediated double-strand break repair

“…tract) (Usdin et al 2015;Neil et al 2017;Polleys et al 2017;Polyzos and McMurray 2017). We and others have also shown that trinucleotide repeat can induce mutagenesis at a distance (RIM-repeat induced mutagenesis) and trigger CGRs (Shah et al 2012;Saini et al 2013;Tang et al 2013).…”

DNA repair in trinucleotide repeat ataxias

“…Recent literature has suggested that DSB may be responsible for large scale expansion in nondividing cells providing a potential mechanism for modification of repeat length and phenotypic variability [90,91]. DSB repair have two major repair pathways: homologous recombination repair (HRR) and nonhomologous end joining (NHEJ) [92].…”

“…While mature postmitotic neurones in G0/G1 rely upon error prone NHEJ, break-induced replication (BIR) of homologous recombination can cause large-scale expansion in a CAG tract repeat cellular model in vitro [31,91]. Importantly, BIR may also occur in nondividing neurons and drive disease progression [91]. BIR is then initiated when a one-ended DSB undergoes 5 0 strand resection followed by invasion into a homologous sequence.…”

“…Homologous recombination uses a sister chromatid as a template to repair a DSB, whereas NHEJ ligates together the two DNA ends with little or no processing [43,46]. While mature postmitotic neurones in G0/G1 rely upon error prone NHEJ, break-induced replication (BIR) of homologous recombination can cause large-scale expansion in a CAG tract repeat cellular model in vitro [31,91]. The TNR expansion occurs during fork stalling resulting from hairpin formation on the single-stranded DNA template.…”

“…This newly invaded strand containing the repetitive tract then serves as a primer for DNA synthesis using DNA polymerase delta (Pold). Importantly, BIR may also occur in nondividing neurons and drive disease progression [91]. A number of autosomal recessive ataxias are driven by genetic mutations in DSB repair genes involved in homologous recombination.…”