Rapid Review

DNA repair in the trinucleotide repeat disorders

Lesley Jones, Henry Houlden, Sarah J Tabrizi

Lancet Neurol 2017; 16: 8896
MRC Centre for
Neuropsychiatric Genetics and
Genomics, Institute of
Psychological Medicine and
Clinical Neurosciences, Cardiff
University, Cardiff, UK
(Prof L Jones PhD); Department
of Molecular Neuroscience and
MRC Centre for Neuromuscular
Diseases, Institute of
Neurology, Queen Square,
London, UK
(Prof H Houlden MD); and UCL
Huntingtons Disease Centre,
Department of
Neurodegenerative Disease,
Institute of Neurology,
University College London,
London, UK (Prof S J Tabrizi PhD)
Correspondence to:
Prof Lesley Jones, MRC Centre for
Neuropsychiatric Genetics and
Genomics, Haydn Ellis Building,
Maindy Road, Cardiff University,
Cardiff CF24 4HQ, UK
jonesl1@cf.ac.uk
Summary
Background Inherited diseases caused by unstable repeated DNA sequences are rare, but together represent a
substantial cause of morbidity. Trinucleotide repeat disorders are severe, usually life-shortening, neurological
disorders caused by nucleotide expansions, and most have no disease-modifying treatments. Longer repeat expansions
are associated with genetic anticipation (ie, earlier disease onset in successive generations), although the dierences
in age at onset are not entirely accounted for by repeat length. Such phenotypic variation within disorders implies the
existence of additional modifying factors in pathways that can potentially be modulated to treat disease.
Recent developments A genome-wide association study detected genetic modiers of age at onset in Huntingtons
disease. Similar ndings were seen in the spinocerebellar ataxias, indicating an association between DNA damage-
response and repair pathways and the age at onset of disease. These studies also suggest that a common genetic
mechanism modulates age at onset across polyglutamine diseases and could extend to other repeat expansion
disorders. Genetic defects in DNA repair underlie other neurodegenerative disorders (eg, ataxia-telangiectasia), and
DNA double-strand breaks are crucial to the modulation of early gene expression, which provides a mechanistic link
between DNA repair and neurodegeneration. Mismatch and base-excision repair are important in the somatic
expansion of repeated sequences in mouse models of trinucleotide repeat disorders, and somatic expansion of the
expanded CAG tract in HTT correlates with age at onset of Huntingtons disease and other trinucleotide repeat
disorders.
Where next? To understand the common genetic architecture of trinucleotide repeat disorders and any further genetic
susceptibilities in individual disorders, genetic analysis with increased numbers of variants and sample sizes is
needed, followed by sequencing approaches to dene the phenotype-modifying variants. The ndings must then be
translated into cell biology analyses to elucidate the mechanisms through which the genetic variants operate. Genes
that have roles in the DNA damage response could underpin a common DNA repeat-based mechanism and provide
new therapeutic targets (and hence therapeutics) in multiple trinucleotide repeat disorders.

Introduction The trinucleotide repeat disorders fall into two main

Trinucleotide repeat disordersinherited diseases
caused by unstable repeated DNA sequenceswere rst
characterised in the 1990s and are individually rare.1
Fragile X syndrome is the most common, with a
prevalence of about one per 4000 boys. Myotonic
dystrophy and Huntingtons disease aect around one
per 10 000 people, and most spinocerebellar ataxias aect
around one per 100 000 people, although the prevalence
of Huntingtons disease and the spinocerebellar ataxias
varies widely across geographical regions. Only a few
cases have been identied for other such disorders.
Together, however, trinucleotide repeat disorders
represent a substantial source of morbidity. Most are
life-shortening and have debilitating symptoms, and no
disease-modifying treatments are available. Although
the mutational mechanisms are similar, the repeated
DNA sequences occur in dierent genomic contexts,
and even in the polyglutamine diseases, where the
repeated codon is translated to glutamine, the proteins
are functionally unrelated. The nature and expression
pattern of the repeat-containing proteins probably leads
to the clinical dierences between these diseases,1 but
the substantial phenotypic variation seen within each
disease remains only partly explained. This variability
can be exploited to gain insights into disease
mechanisms though genetics.2
categories: those in which the repeated sequence is
translated into a protein product and those in which the
repeat lies outside the coding sequence (table 1), but the
non-coding disease-associated repeat sequences are
usually longer than the coding sequences. All the
trinucleotide repeat disorders are associated with genetic
anticipationearlier onset of disease in successive
generations of familiescaused by germline expansion
of the repeat.16 Repeat expansion occurs in dividing and
non-dividing cells, and is tissue specic, cell specic, and
disease specic.1 Expansion of the repeat is ameliorated if
the repeated sequence is interrupted by other codons.
Although associations between repeats and specic loci
have been known since the 1990s, the mechanistic cascade
from repeat to clinical phenotype remains unclear in
trinucleotide repeat disorders, which has hindered the
development of new treatments. Some pathogenic
mechanisms are common to multiple diseases. For
instance, a repeat that prevents gene expression is seen in
fragile X syndrome and Friedreichs ataxia.17 Pathogenic
RNA foci in myotonic dystrophy and myotonic
dystrophy-like 2 give rise to characteristic splicing decits,18
and have been noted in other trinucleotide repeat
disorders, such as myotonic dystrophy 1 and 2.19 Repeat-
associated non-ATG translation, which was rst identied
in myotonic dystrophy and spinocerebellar ataxia 8,20 has

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Gene Repeated Non-expanded Expanded (bp) Somatic expansion Comments

sequence (bp)

5 UTR
Fragile X syndrome3,4 FMR1 CGG <50 >200 Yes (M, H) FRAXE and other rare
fragile sites all CCG
Fragile X-associated tremor/ FMR1 CGG <50 50200 Yes (H, M) ..
ataxia syndrome4
Spinocerebellar ataxia 125 ATXN12 CAG 728 4678 Rare Might also be exonic
Frontotemporal dementia and C9ORF72 GGGGCC 217 1050 kb Yes (H) ..
amyotrophic lateral sclerosis6
Exon
Dentatorubral-pallidoluysian ATN1 CAG <48 48 Yes (H, M) ..
atrophy7
Huntingtons disease8 HTT CAG 635 36250 Yes (H, M) ..
Huntingtons disease-like 29 JPH3 CAG 628 4059 Yes (H) Intronic or 3 UTR also
Spinal and bulbar muscular AR CAG 936 3862 Yes (H, M) ..
atrophy10
Spinocerebellar ataxia 111 ATXN1 CAG 2637 3982 Yes (H, M) ..
Spinocerebellar ataxia 211 ATXN2 CAG 1529 3363 Yes (H, M) Also ALS13*
Spinocerebellar ataxia 311 ATXN3 CAG 1235 4784 Yes (H, M) ..
Spinocerebellar ataxia 611 CACNA1A CAG 716 2029 Rare meiotic ..
Spinocerebellar ataxia 711 ATXN7 CAG 814 3662 Yes (H, M) ..
Spinocerebellar ataxia 1711 TBP CAG 2942 4363 Meiotic ..
Intron
Friedreichs ataxia12 FXN GAA 630 661700 Yes (H, M) ..
Myotonic dystrophy 213 CNBP CCTG <30 5511 000 Yes (H, M) Complex repeat
structure
3 UTR
Myotonic dystrophy 18,13 DMPK CTG 537 100 to 2000 Yes (H, M) ..
Spinocerebellar ataxia 814 ATXN8 (CTA)n (CTG)n <33 80 Yes (H) Might also be exonic;
instability in
non-expanded and
expanded repeats

Only disease-causing repeat loci mentioned in the text are included, so many rare diseases caused by expansion of repeat codons, including those giving rise to shorter
polyalanine tracts,15 are not shown. H=seen in human tissues. M=seen in mouse model tissues. FRAXE=fragile site, folic acid type, rare, Fra(X)(Q28) E genetic locus. *ALS13 is a
disease caused by intermediate repeat lengths in ATXN2.

Table 1: Characteristics of selected disease-causing repeat loci

since been found in Huntingtons disease,21 frontotemporal
dementia and amyotrophic lateral sclerosis (which are
caused by the C9ORF72 hexanucleotide repeat), and other
trinucleotide repeat disorders.22 In frontotemporal
dementia and amyotrophic lateral sclerosis, the C9ORF72
disease-associated repeat dipeptides are neurotoxic,23
although whether such dipeptides have any pathogenic
role in trinucleotide repeat disorders is unknown.
Similar mechanisms might be seen in the
polyglutamine (CAG repeat) diseases;22 however, the
proteins that contain expanded polyglutamine tracts
aggregate and form characteristic insoluble protein
inclusions in neural and other cells in these disorders.
Such insoluble inclusions are also widely seen in other
neurodegenerative disorders,24 which has led to the
hypothesis that they or their soluble oligomers are
pathogenic. So far, the notion that preventing aggregation
can prevent disease in human beings has not been
proven.25 Nevertheless, some ndings hint at this
possibility. For example, in trials of aducanumab, an
antibody that binds and reduces deposition of amyloid ,
cognitive benets were recorded in mouse models and in
clinical studies of people early in the course of
Alzheimers disease.26 Ataxin 1 (ATXN1) oligomers drive
the degenerative eects in spinocerebellar ataxia 1 and
induce local spread of pathology.27 These eects were
partly inhibited with immunotherapy.28 The biological
consequences of expanded polyglutamine have been
extensively studied and a wide range of potentially
harmful outcomes detected,29,30 but which of these are
important in the manifestation of disease remains
unclear. Genetic evidence indicates that the DNA damage
response and DNA repair aect the clinical presentation
of Huntingtons disease and multiple spinocerebellar
ataxias,3133 which suggests that there are common
modiers that act on the mutated repeat itself. Together
with evidence implicating these processes in trinucleotide
repeat disorder biology, these ndings shed light on

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 Rapid Review
specic mechanisms and highlight new targets for
therapeutic intervention.
The DNA damage response and neurological
disease
The DNA damage response (table 2) can be both harmful
and protective in people with neurological diseases.
Mutations in genes involved in the DNA damage response
were rst noted to cause neurological disease in ataxia-
telangiectasia, a rare recessive childhood neuro-
degenerative disease. Mutations in the ataxia-telangiectasia
mutant serine/threonine kinase gene (ATM) cause ataxia-
telangiectasia. This gene controls cell-cycle arrest after
DNA double-strand breaks, often leading to apoptosis
and, thus, neurodegeneration.43 Mutations in other genes
that cause incorrect resolution of DNA double-strand
breaks also lead to severe developmental disorders of the
nervous system, such as ataxia-telangiectasia-like disease,
Seckel syndrome involving the ataxia-telangiectasia and
Rad3-related protein gene (ATR), and Nijmegen breakage
syndrome.42,44 These disorders also have widespread
extraneural eects, in contrast to those resulting from
mutations in genes involved in the repair of DNA single-
strand breaks, which usually have eects limited to the
nervous system, although still with harmful clinical
outcomes.43 Spinocerebellar ataxia with axonal neuropathy
is caused by mutations in the tyrosyl-DNA
phosphodiesterase 1 gene (TDP1) and the recessive
ataxias with oculomotor apraxia 1, 2, and 4 are caused by
mutations in the aprataxin (APTX), senataxin (SETX),
and polynucleotide kinase 3-phosphatase (PNKP) genes,45
respectively. TDP1 repairs stalled topoisomerase IDNA
complexes, APTX and PNKP46 operate on nucleotides,
and SETX encodes a helicase involved in transcriptional
termination.47,48
Most of these recessive diseases result in ataxia with
prominent cerebellar degeneration, which is also seen
DNA break type Mode of repair
Fanconi anaemia Double strand Inter-strand cross-links, possibly other mechanisms34
Homologous recombination Double strand Template-directed end joining from other chromatid35
Non-homologous end joining Double strand Ligates double-strand breaks without a template36
Base-excision repair Single strand Removes damaged bases, lls and ligates the strand37
Direct repair Single strand Direct repair of damaged bases without removal38
Mismatch repair Single strand Corrects mismatches in replication and short insertions
and deletions39
Nucleotide-excision repair Single strand Removes DNA modications that cause structural
distortions40
Translesion synthesis .. Synthesises DNA at sites of damage during replication41
Lesions in DNA result from exogenous and endogenous processes. Repair, irrespective of cause, is fundamental to
genome integrity. Mutations might be induced by damaged bases, structural modications of DNA through
supercoiling, looping out of strands, or inter-strand cross-linking; unrepaired lesions can lead to cell death or
uncontrolled division. Clinically, inherited lesions in the genes involved in the DNA damage response confer
susceptibility to cancers.42 These pathways are distinct, but many of the proteins within them operate in multiple
pathways, which must be borne in mind when considering their potential eects in mediating and modulating
neuropathology.
Table 2: Repair pathways of the DNA damage response
90
in the spinocerebellar ataxias caused by CAG repeat
expansions. Why this outcome should be so remains an
outstanding question. The nervous system is vulnerable
to DNA damage because of its dependence on and high
levels of oxidative metabolism. This process generates
free radicals, which have the potential to cause single-
strand breaks in DNA.44,49 Variation in genes in the DNA
repair machinery can reduce the capacity to repair
single-strand breaks through the modulation of
functional activity, and might, therefore, lead to
neuronal susceptibility. Madabhushi and colleagues50
showed that DNA damage and repair can directly aect
neuronal gene expression: activity-dependent trans-
cription of early-response genes in neurons triggered
the formation of topoisomerase-II-mediated DNA
double-strand breaks in the promoters of these genes.
The products of these early-response genes, such as
c-Fos, regulate multiple downstream pathways and
aect synapses to exert downstream eects on functions
such as cognition, learning, and memory.44 Subtle
variation in these DNA repair proteins could alter the
timing or repair of DNA double-strand breaks. Notably,
individuals carrying mutations in the tyrosyl-DNA
phosphodiesterase 2 gene (TDP2) have intellectual
disability, epilepsy, and ataxia, and deciency of TDP2
(which repairs topoisomerase-induced DNA breaks)
leads to hypersensitivity to topoisomerase-II-mediated
DNA double-strand breaks.51
Conversely, DNA damage-response factors can
maintain appropriate neurological function and be
neuroprotective. Increased DNA double-strand breaks
have been linked to ageing and pathogenesis in
neurodegenerative disorders such as Alzheimers
disease.52 The breast cancer type 1 susceptibility protein
(BRCA1), which resolves DNA double-strand breaks
during homologous recombination,42 is neuroprotective
in mouse models of Alzheimers disease.53 This nding
complements those from earlier studies. For example,
cell models expressing mutant huntingtin (HTT)
accumulate DNA single-strand and double-strand
breaks and display concomitant activation of the DNA
damage response.54 Mutant HTT binds Ku70, a core
component of non-homologous end joining,42 and
overexpression can rescue the phenotype in the
R6/2 model of Huntingtons disease.55 BRCA1 is
recruited to sites of DNA damage by -H2AX. In
Huntingtons disease cell lines, the amount of BRCA1
recruited and the nuclear distribution of -H2AX were
reduced,55 and this eect was rescued by overexpression
of BRCA1.56 Mutant HTT and ATXN1 bind high-mobility
group protein B family proteins that are components of
base-excision repair.42,56 In y and mouse models of
spinocerebellar ataxia 1 with expanded repeats in Atxn1,
neuronal pathology was rescued by expression of high-
mobility group protein B1 (HMGB1), which acted to
reverse mitochondrial DNA damage repair in Atxn1
knockin mouse brains.57,58
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Genetic modiers in the trinucleotide repeat
disorders
One way of overcoming the diculties of interpreting
the cell biology ndings is to return to the study of people
carrying repeat expansions. In natural experiments,2
where conditions are not controlled by the researchers, it
is possible to search for genetic loci that modify disease
in a benecial or deleterious way, and to reveal the
biology that is likely to be relevant to disease
manifestation. For instance, if genetic variation aects
the timing of disease onset or the progression or severity
of disease, drug manipulation of a specic biological
pathway might have similar eects on the disease
phenotype. These types of studies in Mendelian disease
have practical issues that should be considered. By their
nature, trinucleotide repeat disorders are rare and,
therefore, achieving samples large enough to provide
sucient power is challenging. This diculty is being
overcome through networks and consortia that aim to
collect data from large international cohorts of patients,
including DNA and, crucially, systematically collected
clinical information. Two examples are the Enroll study
in Huntingtons disease and the SPATAX consortium in
the spinocerebellar ataxias.59 Even so, for many
trinucleotide repeat disorders the sample sizes will be
small, and the approach of collecting larger and larger
samples to identify relevant genetic loci, as is possible
with common diseases,60 might never be feasible. The
successful search for loci that modify age at onset in
Huntingtons disease, however, suggest that it is.31
Genetic variation that modies rare Mendelian diseases
might be caused by common genetic variants and have
substantial eect sizes. As such, variants might not be
under population selection pressure, as is seen in many
common diseases, and might, therefore, be easier to
nd. Huntingtons disease is relatively common among
rare diseases,61,62 and the collection of DNA and
systematically collected clinical information, such as in
the Registry study of the European Huntingtons Disease
Network,63 has allowed an appropriately powered
genome-wide association study to be done. Three
independent genome-wide loci have been signicantly
associated with age at motor onset, one on chromosome 8
and two close together on chromosome 15, along with a
substantial enrichment of signal in the network of DNA
repair genes.31
Mechanisms related to DNA repair have been
implicated as modulators of somatic expansion of the
disease-associated repeated sequences in mouse models
of Huntingtons disease, myotonic dystrophy,44,64 fragile X
syndrome,65 and Friedreichs ataxia.66 Somatic expansion
and the inverse correlation between CAG repeat length
and age at onset are both widely seen in trinucleotide
repeat disorders (table 1). In the spinocerebellar ataxias
associated with CAG repeats, testing for single-nucleotide
polymorphisms in the DNA repair pathway genes
implicated in Huntingtons disease31 revealed a signicant
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Rapid Review
genetic signal in the same direction.32 Thus, at least some
genetic modiers in the DNA repair pathways seem to
act at the level of the mutation type (ie, the repeated
sequence itself) rather than aecting the functions of
individual trinucleotide repeat disorder proteins.
Modication might arise through the somatic expansion
seen in many trinucleotide repeat disorders. In myotonic
dystrophy type 1, somatic expansions have been detected
in blood and other tissues. This discovery enabled
Morales and colleagues67 to identify polymorphisms in
the mutS homolog 3 gene (MSH3) in a cohort in Costa
Rica, which they found were associated with variation in
somatic instability in blood, although they did not
identify any association with age at onset. Nevertheless,
this nding indicates an intriguing direct link between
DNA repair gene polymorphisms and somatic instability
of repeats, and supports the idea that mismatch repair is
central to repeat expansion.
DNA repeat expansions and the DNA damage
response
Repeat expansions in DNA are aected directly by For the Enroll study in
activities of the DNA damage response (table 2).8 The Huntingtons disease see
https://www.enroll-hd.org/
repeats undergo expansion on transmission through the
germline, in dividing and terminally dierentiated
somatic cells, and the repeat size increases with age.8
Strand breakage in the repeat is repaired, and it is at this
point the repeat sequences are thought to expand.64,68 The
length of the repeat expansion in Huntingtons disease
correlates positively with the propensity for further
somatic expansion,69 with the greatest expansions
occurring in the striatum, which might explain why the
striatum is particularly susceptible to degeneration in
this disorder.70 Proteins containing polyglutamine
expansions can bind nuclear proteins that operate in
DNA repair, such as valosin-containing protein (VCP) or
transitional endoplasmic reticulum ATPase (TERA),71
which raises the possibility that accumulation of the
expanded polyglutamine proteins induces DNA damage.
If true, disease pathogenesis might be exacerbated in a
vicious cycle.
The structure of the repeats aects the likelihood of
expansion. Trinucleotide repeats can adopt multiple
incorrectly paired structures, including hairpins, loops,
triplet helices, and G-quadruplexes (gure).68,72 Bulky
non-B DNA structures might be stable at large sizes73 and,
therefore, act as substrates for the DNA damage response.
The CTGCAG repeat sequence adopts multiple transient
slipped-DNA junctions, leading to unpaired bases that
could be targets of DNA repair. In support of this
possibility, the prevalence of slipped-strand features
correlates with the degree of instability in tissues from
patients with myotonic dystrophy type 1.74 RNADNA
hybrids (R-loops) that are formed during transcription-
coupled nucleotide-excision repair prevent repeat
contraction and knock down of SETX, which controls
resolution of R-loops and increases repeat instability in
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human cell models.75 Damage to individual bases also
requires repair, and oxidative damage from the generation
of reactive oxygen species through mitochondrial
dysfunction and excitotoxicity, as is seen in Huntingtons
disease, can lead to the formation of aberrant DNA
adducts and induction of the DNA damage response.29
Such damage might also be potentiated by the expanded
repeats themselves through repeat-induced mutagenesis.76
The mechanisms of germline and somatic expansion
might involve dierent pathways, because replication is
also associated with repeat expansion.77 In non-dividing
cells, such as neurons, DNA repair activities and
expansion are thought to be associated with DNA damage,
transcription, and chromatin dynamics, although some
evidence suggests that environmental stress induces
DNA re-replication and promotes repeat expansion.78
Mismatch repair
Mismatch repair activity on DNA modulates somatic
expansion of repeat tracts (gure),8 and elements of the
classic mismatch repair pathways might also act as
downstream eectors of other DNA repair mechanisms.
In mammalian cells, two complexes are involved in
mismatch repair: MutS, which contains mutS
homolog 2 (MSH2) and mutS homolog 6 (MSH6) and
preferentially targets mismatched bases, and MutS,
which contains MSH2 and MSH3 and preferentially
targets small insertion-deletions.42,64 The MutS complexes
recruit the endonuclease MutLa, which is a complex of
mutL homolog 1 (MLH1) and mismatch repair system
component PMS1 homolog 2 (PMS2), and cleaves the
DNA of the lesioned strand;64 this action can also be
performed by the MutL complex of MLH1 and
mismatch repair system component PMS1, and the
MutL complex of MLH1 and MLH3. MutS can cause
somatic and intergenerational CAGCTG repeat
instability, but the evidence for MutS is less consistent.64
Knock out of repair genes prevents somatic expansion
and ameliorates the phenotype of Huntingtons disease
in mice.79,80 Susceptibility to somatic expansion was
mapped to Mlh1 and Mlh3 in mouse chromosome
substitution experiments,81 and Huntingtons disease
mouse crosses in dierent background strains showed
that increased concentrations of MSH3 were associated

A Mismatch repair of slipped strands B Transcription-coupled nucleotide-excision C Bulky structures detected by the Fanconi
repair of RNA-DNA hybrids anaemia pathway (hypothetical)
DNA Repeat DNA
Stalled
Hairpins
transcription G-quadruplexes, triple helices
Cruciforms
RNA
Loops TOPOII-mediated
promotor cleavage R-loops
MutS cleavage
FAN1 binding and cleavage by MLH1
MutS-directed and MutS-directed cleavage might be involved in repair

D Base-excision repair of damaged bases

Damage
DNA synthesis across repeat
RIM

OGG1/FEN1 cleavage

Damage to bases might be induced by environmental

and excitotoxic eects and oxidative stress

Figure: DNA repair and repeat expansion mechanisms potentially contributing to repeat instability
DNA mismatch repair (A), transcription-coupled nucleotide-excision repair (B), the Fanconi anaemia pathway (C), and base-excision repair (D) might all have roles
in repeat instability. Slipped strands of dierent sizes can occur in CAG repeats, in which CG bases are Watson-Crick paired and stabilise the looped-out structures,
but the intervening bases are not paired; unpaired bases also occur at the ends of loop structures and at bulges in the DNA, as shown in parts AC. These unpaired
bases are susceptible to damage, which can lead to base-excision repair (D). Transcription-coupled repair can occur as the DNA strands separate for transcription and
the DNA on the non-transcribed strand is unwound and exposed. Elements of the transcriptional machinery can cleave the DNA, and stalled transcription promotes
the formation of R-loops, which predispose to repeat instability (B). In the Fanconi anaemia pathway, FAN1, a structure-specic nuclease, and possibly other
elements of this pathway, might recognise and bind to bulky structures formed by the repeat sequences, such as G-quadruplexes, leading to DNA cleavage that
renders repair necessary and predisposes to repeat instability (C). However, no mechanistic work exists to support this hypothesis. All the DNA structures with
unpaired bases are likely to have an increased propensity for DNA damage, and extrinsic and intrinsic factors, such as oxidative stress, are likely to cause further
harm. Such damage and subsequent base-excision repair leads to DNA repair by gap-lling synthesis, and predisposes to instability of repeats.
TOPOII=topoisomerase II. RIM=repeat-induced mutagenesis.

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with repeat expansion.82 In cells carrying 800 CAGCTG
repeats, knock down of MSH2 and MSH3 prevented
repeat expansion.74 Similar phenomena are also apparent
in models of Friedreichs ataxia and fragile X syndrome
in mice, carrying, respectively, GAATTC and CGGCCG
expansions,83,84 and DNA damage-response genes are
downregulated in the blood of patients with fragile X
syndrome.85 A further nding of note is that histone
deacetylase enzymes promote repeat expansion via the
MutS pathway.86 CAG repeat sequences show enhanced
convergent transcription (ie, transcription taking place
on both strands with RNA polymerases moving
towards each other),87 which involves mismatch repair
components but induces cell death via ATR focus
formation.88 The nal pathways of neurodegeneration
and cell death in the trinucleotide repeat disorders might,
therefore, parallel those of other neurological diseases,
such as the ataxia-telangiectasia-like diseases that can be
caused directly by mutations in ATR.
Base-excision repair
The response to oxidative damage of DNA by base-
excision repair aects repeat expansion (gure).
8-Oxoguanine glycosylase (OGG1) removes 8-oxoguanine
bases from DNA that has been damaged through the
action of reactive oxygen species. Crossing Huntingtons
disease knockin mice with Ogg1-decient mice reduces
somatic expansion of the CAG repeat in Htt and delays
onset of symptoms. Treatment of mice with a reactive
oxygen species scavenger to prevent DNA oxidation
reduces somatic expansion and leads to improvement of
the motor phenotype.89 Flap endonuclease 1 (FEN1) also
has a role in base-excision repair and repeat expansion.90
During base-excision repair of 8-oxoguanine in the DNA
of CAG repeats, OGG1 and mutY DNA glycosylase
(MUTYH), which remove adenine incorporated opposite
unrepaired 8-oxoguanine bases, generate incisions on
opposite DNA strands that might permit repeat
expansion,91 although events downstream of DNA
cleavage are also involved in expansions. For instance, the
protein product of the ribonuclease reductase regulator
TP53 inducible subunit M2B gene (RRM2B) is induced
in brain regions that show somatic expansion of repeats
in the R6/2 mouse model of Huntingtons disease, but
not in those that do not.91 Of note, RRM2B is in the
genome-wide signicant peak on chromosome 8 in the
Genetic Modiers of Huntingtons Disease (GeM-HD)
study,31 and has nominal associations in other
trinucleotide repeat disorders.32
The Fanconi anaemia repair pathway
The role of the Fanconi anaemia pathway34 in trinucleotide
repeat disorders is unexplored. However, the
chromosome 15 locus associated with age at onset of
Huntingtons disease31 contains FAN1. The product of
this gene, the DNA nuclease FAN1, is a candidate for
modifying the onset of Huntingtons disease through the
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Rapid Review
mechanisms parallel to the topoisomerase-II cleavage
suggested by Madabhushi and colleagues,50 or by
promoting or lessening DNA expansion at the CAG
repeat. FAN1 cleaves DNA at inter-strand cross-links, and
is involved in repair in combination with other members
of the Fanconi anaemia pathway, including FANCD2 and
the mismatch repair proteins.34 Mutations in genes
associated with inter-strand cross-link repair cause
Fanconi anaemia, but loss-of-function mutations in FAN1
lead to the recessive renal syndrome and karyomegalic
interstitial nephritis,92 and heterozygous truncating
mutations cause some familial colorectal cancers,93
similar to other mismatch repair pathway mutations.
Rather than recognising specic DNA sequences, FAN1
recognises branched structures that mimic DNA repair.34,94
Repeat sequences, including CAG repeats, adopt non-
helical structures in DNA, such as G-quadruplexes,68 and
FAN1 might target these structures rather than the DNA
sequence itself (gure). This DNA repair activity is
probably dependent on other mismatch repair proteins,
which would be consistent with the manipulation of
mismatch repair genes ameliorating Huntingtons
disease phenotypes in mice.64 Given that MLH1 is in a
locus on chromosome 3 that has a signal just below
genome-wide signicance in the Huntingtons disease
genome-wide association study,31 and MLH1 interacts
with FAN1, this gene and these proteins might have
central roles in a novel FAN1-driven activity that binds
repeats and modulates their instability.
Conclusions and future directions
Showing that genetic modiers exist in Mendelian
trinucleotide repeat disorders demonstrates that nding
genetic modiers in rare genetic diseases is possible, and
highlights areas of biology that modulate disease in
people, such as specic aspects of the DNA damage
response: mismatch repair, base-excision repair, and the
Fanconi anaemia pathway. The ndings raise two
important questions. The rst is whether genetic
association with DNA repair processes occurs across all
the trinucleotide repeat disorders, and the second is
whether there is a common mechanism underlying
somatic expansion of repeats. To establish the relevance
of DNA repair and other modiers to the trinucleotide
repeat disorders, more genetic studies, including
genome-wide association and sequencing studies, are
needed to provide adequate power to identify risk-related
single-nucleotide polymorphisms and loci. Many of the
repeat diseases have very long repeats that are dicult to
measure accurately, but new sequencing technologies,
including long-read and single-cell sequencing, should
overcome this diculty and improve accuracy in
determining the exact sequence in the repeat, including
any interruptions.95 Work being done in Huntingtons
disease and other polyglutamine diseases suggests that
combining multiple diseases in one analysis might be a
possible route to increasing power.32
93
 Rapid Review
Search strategy and selection criteria
We searched PubMed for papers published from Jan 1, 2012, to
Sept 30, 2016, using combinations of the terms huntingt*,
spinocerebellar ataxia, trinucleotide repeat, triplet repeat,
repeat, or repeat disease, and DNA integrity, DNA
repair, genome integrity, or genome repair. Our search was
limited to publications that included search terms in the title,
abstract, or both. We identied further relevant papers by
searching the reference lists of retrieved papers and through
searches of our les. The nal reference list was based on
relevance to the topic of this Rapid Review.
Elucidating the mechanistic consequences of genetic
variation will be challenging. Cell and animal models of
many of the trinucleotide repeat disorders are already
available, and could be rened with knowledge of genetic
modiers and common biology. Such knowledge will
allow development of common downstream assays that
reect the disease biology that is important in human
beings. So far, however, there is no information about
the direct molecular eects of the genetic variation
detected. Thus, whether the function of the DNA
damage response is improved or inhibited by these
changes is unknown. As in complex diseases, clues can
be gathered by aggregating data about likely changes in
expression and the functional eects of coding changes
in genes and pathways, and using genome-wide data,
such as co-expression networks96 and protein-interaction
networks.97
Downstream from genetic discovery, to establish
whether somatic expansion or other DNA repair or
integrity mechanisms are responsible for the genetic
signal, cell biology and animal studies will be necessary.
Human tissue will be needed to investigate gene
expression and to show the eects of the variants in vivo.
One immediate priority is establishing the eects of
manipulating the Fanconi anaemia pathway, and work in
this area is just beginning. Potential emerging pathogenic
mechanisms that require further investigation include
the operation of repeat-induced mutagenesis, where DNA
repair activities lead to further mutagenesis around
repeat loci,76 and the relevance of chromatin structure to
repeat exposure and dynamics.98 Detailing the exact
nature of the mechanisms of the DNA damage response
essential in neurodegeneration will allow the development
of new drugs and possibly the repurposing of existing
treatments that target the DNA damage response in
cancers.42
Finally, mechanisms common to multiple diseases
oer hope that treatments can be developed that will be
applicable across disorders. This approach can be seen in
the case of cancers, where common biological pathways
are dysregulated in multiple forms of the disease, and
the same chemotherapeutic agents can be used in
dierent regimens to treat various cancers.99 The ndings
94
presented in this Rapid Review open a new window on
repeat expansion disease, with obvious avenues for
therapeutic exploitation.
Contributions
LJ did the literature search, wrote the rst draft of the review, and
prepared the gures and tables. HH and SJT edited the drafts and
suggested additional ndings from their knowledge of the literature.
Declaration of interests
We declare no competing interests.
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