Key Points
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Trinucleotide expansion in human disease occurs at different stages and in different cell types during development. The status of cell division determines the mechanism of expansion.
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Large expansions occur in non-dividing cells. Large repeat tracts are deleted in spermatogonia.
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Pre-mutation alleles can expand or contract in dividing and non-dividing cells.
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In non-dividing cells, expansion is likely to occur during excision repair. Candidate pathways are base excision repair or transcription-coupled repair.
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Oxidative damage of DNA bases is corrected by base excision repair and expansion occurs during the process of removing oxidized bases. Loss of 7,8-dihydro-8-oxoguanine DNA glycosylase (OGG1, also known as N-glycosylase/DNA lyase) in mice suppresses expansion.
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Cockayne syndrome protein CSB (also known as ERCC6) and xeroderma pigmentosum complementation group G (XPG) have been implicated in instability of CAG repeats in flies and in human cells.
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In dividing cells, replication dependent repair mechanisms, such as polymerase 'back-up' and trans-lesion synthesis, are candidates for causing expansion.
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Expansion is a two-step process in which DNA loops are formed and then incorporated into DNA. The two steps may occur by distinct mechanisms.
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The mismatch repair system may be involved in forming the DNA loops that become expansions and may also be involved in loop incorporation into DNA.
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Progress in this field will require the integration of various strategies, including genetic and biochemical methods and analysis of DNA repair crosstalk and chromatin dynamics.
Abstract
Trinucleotide expansion underlies several human diseases. Expansion occurs during multiple stages of human development in different cell types, and is sensitive to the gender of the parent who transmits the repeats. Repair and replication models for expansions have been described, but we do not know whether the pathway involved is the same under all conditions and for all repeat tract lengths, which differ among diseases. Currently, researchers rely on bacteria, yeast and mice to study expansion, but these models differ substantially from humans. We need now to connect the dots among human genetics, pathway biochemistry and the appropriate model systems to understand the mechanism of expansion as it occurs in human disease.
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Acknowledgements
I would like to thank J. Majka, V. Platt, W. Lang, E. Xun, C. Canaria and S. Bernstein for critical discussions and comments. This work is supported by US National Institutes of Health grants NS062384, NS40738, GM066359, NS060115, NS069177 and CA092584.
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Glossary
- Threshold length
-
In the context of trinucleotide repeat alleles, the number of trinucleotide repeats at which the tract becomes unstable.
- Pre-mutation
-
The length of a pre-mutation trinucleotide repeat tract is within the normal range, but the pre-mutation allele has increased susceptibility to mutation in a subsequent transmission. Individuals with a pre-mutation allele will exhibit a normal phenotype but may have offspring who have a higher number of trinucleotide repeats and who might be affected by the disease.
- Anticipation
-
The propensity of trinucleotide repeats above a certain threshold to increase (expand) during transmission to offspring, often causing increases in disease severity and decreases in the age of onset.
- Fragile X syndrome
-
(Also known as Martin–Bell syndrome.) A genetic disorder caused by the expansion of a single trinucleotide gene sequence (CGG) on the X chromosome, which leads to loss of expression of the FMR1 gene.
- Full mutation
-
A repeat tract that is unstable and of a length that is typically associated with disease. The term is often used to distinguish such cases from alleles of a shorter, pre-mutation length that are not associated with disease.
- Normal length
-
In the context of trinucleotide repeat alleles, the range of repeat lengths in which the repeat tract is stable as the gene is passed to the next generation.
- Myotonic dystrophy type 1
-
(Also known as Steinert's disease.) A chronic, slowly progressive, inherited, multi-systemic disease that has a severe congenital form and a milder childhood-onset form.
- Huntington's disease
-
A neurodegenerative disease that is caused by an abnormal trinucleotide repeat (CAG) in the huntingtin (HTT) gene. Uncoordinated, involuntary movements and decline in mental cognition characterize the disease.
- Homologous recombination
-
A type of genetic recombination in which nucleotide sequences are exchanged between two similar or identical molecules of DNA. It is most widely used by cells to accurately repair harmful breaks that occur on both strands of DNA (known as double-strand breaks).
- Crossover
-
The exchange of material between two chromosomes. It is one of the final phases of genetic recombination and occurs during prophase I of meiosis (diplotene) in a process called synapsis. Crossover usually occurs when matching regions on matching chromosomes break and then reconnect to the other chromosome.
- Non-homologous end joining
-
A pathway that repairs double-strand breaks in DNA using a non-homologous chromosome. It typically uses short homologous DNA sequences, called microhomologies, to guide repair. Microhomologies are often present in single-strand overhangs on the ends of double-strand breaks.
- Base excision repair
-
The cellular mechanism that is primarily responsible for removing small, non-helix-distorting base lesions from the genome. It is important for removing damaged bases that could otherwise cause mutations by mispairing or lead to breaks in DNA during replication.
- Long patch
-
In the context of base excision repair, long patch repair is when the gap-filling polymerase induces strand displacement at the single-strand break and restores normal Watson–Crick pairing by replacing a patch of two to 15 nucleotides.
- Short patch
-
In the context of base excision repair, short patch repair is when the gap-filling polymerase replaces the damaged base with a single nucleotide to restore normal Watson–Crick pairing.
- Polymerase β
-
The major DNA repair polymerase that is used in base excision repair.
- Polymerase δ
-
The major polymerase that copies DNA on the discontinuous or lagging strand template during cell proliferation.
- Polymerase ɛ
-
The major polymerase that copies the leading strand template during cell proliferation.
- Apurinic
-
A site in duplex DNA that has lost guanine or adenine.
- Polymerase slippage
-
The misalignment of the DNA polymerase during cell proliferation, typically at repetitive DNA sequences. Misalignment on the template strand causes a loss in DNA bases and misalignment on the daughter strand leads to a gain in DNA bases.
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McMurray, C. Mechanisms of trinucleotide repeat instability during human development. Nat Rev Genet 11, 786–799 (2010). https://doi.org/10.1038/nrg2828
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DOI: https://doi.org/10.1038/nrg2828
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