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Review
. 2018 Jan 30;11(1):dmm031930.
doi: 10.1242/dmm.031930.

The central role of DNA damage and repair in CAG repeat diseases

Thomas H Massey  1 , Lesley Jones  2
Affiliations
Review

The central role of DNA damage and repair in CAG repeat diseases

Thomas H Massey et al. Dis Model Mech. .

Abstract

Diseases such as Huntington's disease and certain spinocerebellar ataxias are caused by the expansion of genomic cytosine-adenine-guanine (CAG) trinucleotide repeats beyond a specific threshold. These diseases are all characterised by neurological symptoms and central neurodegeneration, but our understanding of how expanded repeats drive neuronal loss is incomplete. Recent human genetic evidence implicates DNA repair pathways, especially mismatch repair, in modifying the onset and progression of CAG repeat diseases. Repair pathways might operate directly on repeat sequences by licensing or inhibiting repeat expansion in neurons. Alternatively, or in addition, because many of the genes containing pathogenic CAG repeats encode proteins that themselves have roles in the DNA damage response, it is possible that repeat expansions impair specific DNA repair pathways. DNA damage could then accrue in neurons, leading to further expansion at repeat loci, thus setting up a vicious cycle of pathology. In this review, we consider DNA damage and repair pathways in postmitotic neurons in the context of disease-causing CAG repeats. Investigating and understanding these pathways, which are clearly relevant in promoting and ameliorating disease in humans, is a research priority, as they are known to modify disease and therefore constitute prevalidated drug targets.

Keywords: CAG repeat; DNA damage; DNA repair; Huntington's disease; Spinocerebellar ataxia.

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Conflict of interest statement

Competing interestsThe authors declare no competing or financial interests.

Figures

Fig. 1.
Fig. 1.
DNA double-strand break repair pathways in neurons, highlighting key similarities and differences. (A) Homologous recombination is utilised in S or G2 phase of dividing neuronal progenitors. DNA ends are processed by MRN complexes and other proteins to produce 3′-overhangs coated by RPA proteins. BRCA2 catalyses the exchange of RPA for RAD51, thus enabling invasion of the sister chromatid and error-free repair. (B) Nonhomologous end joining is utilised by postmitotic neurons in G0 or G1. DNA ends are bound by KU70/80, leading to the recruitment of DNA-PKcs. End processing is carried out by various enzymes including PNKP and Artemis (DCLRE1C), and then ends are ligated by LIG4-XRCC4. This form of repair preserves genomic integrity but can be error prone. Proteins at key commitment points are shown in colour, others in grey boxes. Some factors involved in double-strand break repair and cell-cycle regulation are omitted for clarity. BRCA2, breast cancer type 2 susceptibility protein; CtIP, C-terminal binding protein 1 interacting protein; DNA-PKcs, DNA-dependent protein kinase, catalytic subunit; MRN complex, MRE11-RAD50-NBS1 complex; LIG, DNA ligase; PCNA, proliferating cell nuclear antigen; PNKP, polynucleotide kinase 3′-phosphatase; RPA, replication protein A; TDP1, tyrosyl-DNA phosphodiesterase 1; XLF, XRCC4-like factor; XRCC4, X-ray repair cross-complementing 4.
Fig. 2.
Fig. 2.
Similarities and differences between the principal mammalian single-strand DNA damage repair pathways. Examples of cell stressors are shown, with resultant DNA damage. DNA repair proceeds through a conserved general mechanism of damage recognition, lesion excision and processing, DNA repair synthesis and ligation of DNA ends, as shown from top to bottom. Components vary between pathways although there is considerable overlap. The four main repair pathways for single-strand DNA lesions are shown, with the key proteins involved. (A) Mismatch repair (MMR). (B) Base excision repair (BER). (C) Nucleotide excision repair (NER). (D) Single-strand break repair (SSBR). AP endonuclease, apurinic/apyrimidinic endonuclease 1; CSA/CSB, Cockayne syndrome protein A/B; ERCC1, excision-repair cross-complementing 1; FEN1, flap endonuclease 1; GG-NER, global genomic nucleotide excision repair; HR23B, human RAD23 homologue B; LIG, DNA ligase; MLH, MutL protein homologue; MSH, MutS protein homologue; PARP, poly(ADP-ribose) polymerase; PMS2, postmeiotic segregation increased 2; PNKP, polynucleotide kinase 3′-phosphatase; Pol, DNA polymerase; TC-NER, transcription-coupled nucleotide excision repair; TFIIH, transcription factor IIH; UV, ultraviolet; XPA/XPC/XPD/XPF/XPG, DNA repair proteins in different xeroderma pigmentosum (XP) complementation groups; XRCC1, X-ray repair cross-complementing 1.
Fig. 3.
Fig. 3.
DNA damage and repair can affect CAG repeat length with downstream effects on disease pathogenesis. CAG repeats in DNA are unstable, and cycles of DNA damage and repair can lead to changes in repeat length. (A) Wild-type length repeats can expand to (B) intermediate lengths, stochastically. These will mostly be repaired to wild-type length (black, bold arrow from B to A), perhaps through a dedicated pathway, but a small number will expand further (C) into the disease-associated range in gametes. (D) Once over the disease-causing threshold, repeats are predisposed to expand further (black, bold arrow from C to D) in both germline and somatic cells. In addition to the role of DNA repair in repeat length changes, some genes containing CAG repeats encode proteins with roles in DNA repair. Expanded repeats can impair the functions of these DNA repair proteins, leading to the accrual of DNA damage in neurons and to a toxic cycle of DNA damage/repair and repeat expansion (red dashed arrows). DNA repair variants associated with earlier or later disease onset could affect any of these processes.
Fig. 4.
Fig. 4.
Putative roles of HTT and ATXN3 in DNA repair and how HTT and ATXN3 polyglutamine expansions might lead to DNA damage and apoptosis. (A) Wild-type HTT and ATXN3 proteins have various roles in the DNA damage response, as illustrated. ROS that cause DNA damage also induce the nuclear translocation of both HTT and ATXN3 (solid arrows), as well as specific HTT phosphorylation. In the nucleus, HTT is recruited to sites of DNA damage by ATM, and can act as a scaffold for DNA repair processes. Nuclear ATXN3 can bind to and stimulate the DNA end-processing repair factor, PNKP, as well as altering gene expression as part of the cellular stress response. HTT and ATXN3 also have functions in regulation of autophagy. Repair processes and their associated factors are shown in green. (B) In HD or (C) in SCA3, disease-length polyglutamine expansions (depicted as red, Qn) can inhibit DNA repair processes, leading to the accrual of DNA damage in cells. In both of these diseases, the mutated proteins can sequester DNA repair factors in the cytoplasm (ATM in HD, PNKP in SCA3), away from sites of DNA damage. Persistent DNA damage and signalling can result in p53-mediated apoptosis; in HD, via dominant-negative hypophosphorylated mutant HTT at sites of DNA damage; in SCA3 via chronic activation of ATM by mutant ATXN3. Nonfunctional ATM and PNKP are crossed in the figure. ATM, ataxia telangiectasia mutated; ATXN3, ataxin-3; HD, Huntington's disease; HTT, huntingtin; PNKP, polynucleotide kinase 3′-phosphatase; ROS, reactive oxygen species; SCA3, spinocerebellar ataxia type 3.
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References

    1. Aboussekhra A. and Thoma F. (1999). TATA-binding protein promotes the selective formation of UV-induced (6-4)-photoproducts and modulates DNA repair in the TATA box. EMBO J. 18, 433-443. 10.1093/emboj/18.2.433 - DOI - PMC - PubMed
    1. Abraham K. J., Chan J. N. Y., Salvi J. S., Ho B., Hall A., Vidya E., Guo R., Killackey S. A., Liu N., Lee J. E. et al. (2016). Intersection of calorie restriction and magnesium in the suppression of genome-destabilizing RNA–DNA hybrids. Nucleic Acids Res. 44, 8870-8884. 10.1093/nar/gkw752 - DOI - PMC - PubMed
    1. Anne S. L., Saudou F. and Humbert S. (2007). Phosphorylation of huntingtin by cyclin-dependent kinase 5 is induced by DNA damage and regulates wild-type and mutant huntingtin toxicity in neurons. J. Neurosci. 27, 7318-7328. 10.1523/JNEUROSCI.1831-07.2007 - DOI - PMC - PubMed
    1. Ashkenazi A., Bento C. F., Ricketts T., Vicinanza M., Siddiqi F., Pavel M., Squitieri F., Hardenberg M. C., Imarisio S., Menzies F. M. et al. (2017). Polyglutamine tracts regulate beclin 1-dependent autophagy. Nature 545, 108-111. 10.1038/nature22078 - DOI - PMC - PubMed
    1. Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium (2017). Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia. Mol. Autism 8, 21 10.1186/s13229-017-0137-9 - DOI - PMC - PubMed

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