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Review
. 2017 Sep;39(9):10.1002/bies.201700077.
doi: 10.1002/bies.201700077. Epub 2017 Jul 13.

Precarious maintenance of simple DNA repeats in eukaryotes

Alexander J Neil  1 , Jane C Kim  2 , Sergei M Mirkin  1
Affiliations
Review

Precarious maintenance of simple DNA repeats in eukaryotes

Alexander J Neil et al. Bioessays. 2017 Sep.

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.

Keywords: DNA microsatellites; break-induced replication; centromeres; replication fork stalling; telomeres; template switching; trinucleotide repeats.

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Figures

Figure 1
Figure 1
DNA structures formed by simple DNA repeats. A: H-DNA formed by GAA/TTC sequences. As shown, the homopurine (GAA) strand is donated to the triplex. Dots indicate Watson-Crick base pairing. Asterisks indicate reverse Hoogsteen base pairing. B: Imperfect hairpin formed by (CNG)n repeats. C: G-quadruplex formed by (CGG)n repeats. Grey squares represent hoogsteen basepairing between four guanines. D: The G-rich strand of telomeres can form G guadruplex structures. One possible example is shown here. The T-loop results from invasion of the single-stranded telomeric 3′-overhangs into the upstream telomeric duplex DNA.
Figure 2
Figure 2
Mechanisms of small-scale repeat expansion. A: The flap ligation model of repeat expansion. The lagging strand polymerase (Polδ) performs displacement synthesis on the preceding Okazaki fragment leading to the formation of a 5′ flap. Formation of a hairpin structure within the flap precludes flap processing. Subsequent ligation of the hairpin flap to the adjacent Okazaki fragment results in a strand asymmetry that can lead to expansion upon the next round of replication. B: The replication slippage model of repeat expansion. The leading strand polymerase (Polε) slips within the repetitive sequence resulting in the formation of a hairpin on the nascent strand. This hairpin can be duplicated into an expansion upon the next round of replication. Slippage can occur on either the leading or lagging strands.
Figure 3
Figure 3
Two mechanisms of template switching. A: Template switching at a stalled replication fork occurs when the leading strand polymerase (Polε) encounters a lesion (yellow star) in the DNA template. Stalling of the leading strand polymerase leads to fork uncoupling as the lagging strand continues to be replicated. Fork stalling triggers the DNA damage response after replication protein A (RPA, red spheres) is recruited to single stranded DNA. Lesion bypass is primed by the nascent leading strand using Polδ and the nascent lagging strand as a homologous template. B: Template switching behind a replication fork is instigated by stalling of the lagging strand polymerase (Polδ) at a lesion in the DNA template (yellow star). The discontinuity of lagging strand replication allows fork progress to continue and template switching can occur without stalling using the nascent leading strand as a template.
Figure 4
Figure 4
Proposed mechanism of large-scale GAA/TTC repeat expansion. Green = GAA repeats. Red = TTC repeats. A: Displacement synthesis by the lagging strand polymerase (Polδ) leads to the formation of a 5′ flap that can be processed by the flap endonuclease Fen1. B: In some circumstances (especially in the absence of Fen1) the displaced 5′ flap folds back, forming a triplex that blocks further synthesis by Polδ. C: Polδ switches template to the nascent leading strand in order to bypass the 5′ flap triplex and continue Okazaki fragment synthesis. D: Ligation of the extended Okazaki fragment to the folded back 5′ flap triplex resolves the template switching event and leads to a strand asymmetry that results in repeat expansion upon the next round of replication.
Figure 5
Figure 5
Proposed mechanism of large-scale CAG/CTG repeat expansion. Blue = CAG repeats. Brown = CTG repeats. A: CTG hairpin formation on the leading strand template stalls the replication fork by blocking Polε. B: Reversal of the replication fork leads to a four-way junction that can be recognized by the Holliday-junction endonucleases Mus81 and Yen1. C: Cleavage of the reversed fork leads to a one-ended double strand break that undergoes end section via the Mre11-Rad50-Nbs1/Xrs2 (MRN) complex. D: “Out-of-register” strand invasion between repetitive sequences mediated by Rad51 is encouraged by hairpin formation in the invading strand and primes break-induced replication (BIR) synthesis. E: BIR synthesis by Polδ proceeds as a migrating D-loop and is aided by Pif1 helicase through the repetitive tract until it encounters an oncoming replication fork at which point resolution requires cleavage by an endonuclease [17]. BIR synthesis is conservative as newly synthesized DNA extruded from the D-loop templates duplication of CTG repeats. F: Resolution of the BIR process results in repeat expansion in a single step.
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