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Abnormal base excision repair at trinucleotide repeats associated with diseases: a tissue-selective mechanism.

Goula AV, Merienne K - Genes (Basel) (2013)

Bottom Line: The mutation is unstable and further expands in specific cells or tissues with time, which can accelerate disease progression.DNA damage and base excision repair (BER) are involved in repeat instability and might contribute to the tissue selectivity of the process.In this review, we will discuss the mechanisms of trinucleotide repeat instability, focusing more specifically on the role of BER.

View Article: PubMed Central - PubMed

Affiliation: Programme of Translational Medicine and Neurogenetics, Institute of Genetics and Molecular and Cellular Biology (IGBMC), UMR 7104-CNRS/INSERM/Uds, 1 rue Laurent Fries, 67404 Illkirch, France. agathi.goula@hotmail.fr.

ABSTRACT
More than fifteen genetic diseases, including Huntington's disease, myotonic dystrophy 1, fragile X syndrome and Friedreich ataxia, are caused by the aberrant expansion of a trinucleotide repeat. The mutation is unstable and further expands in specific cells or tissues with time, which can accelerate disease progression. DNA damage and base excision repair (BER) are involved in repeat instability and might contribute to the tissue selectivity of the process. In this review, we will discuss the mechanisms of trinucleotide repeat instability, focusing more specifically on the role of BER.

No MeSH data available.


Related in: MedlinePlus

Base excision repair (BER)-induced CAG repeat expansion is tissue-dependent. Oxidative DNA lesions, including 8-oxoG lesions, occur stochastically at trinucleotide CAG repeats and are processed by the BER pathway. A DNA glycosylase (e.g., Ogg1) and Ape1 initiate repair. Repair outcome (“no expansion” or “expansion”) is dependent upon the location of the lesion and the tissue that is repaired. In the cerebellum, where Fen1 and Lig1 are abundant, the DNA lesion at CAG repeats is correctly repaired: the flappy structure resulting from multinucleotide incorporation by Polβ during long-patch (LP)-BER by Fen1 is efficiently processed, and the subsequent ligation step does not result in expansion. In contrast, in the striatum, where Fen1 and Lig1 proteins are reduced, repair of the DNA lesion at CAG repeats is error-prone. The flappy structure is not efficiently processed, which ultimately leads to repeat expansion through a yet unknown mechanism. Additional DNA repair pathways, including mismatch repair (MMR), might interplay with BER during this process.
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genes-04-00375-f001: Base excision repair (BER)-induced CAG repeat expansion is tissue-dependent. Oxidative DNA lesions, including 8-oxoG lesions, occur stochastically at trinucleotide CAG repeats and are processed by the BER pathway. A DNA glycosylase (e.g., Ogg1) and Ape1 initiate repair. Repair outcome (“no expansion” or “expansion”) is dependent upon the location of the lesion and the tissue that is repaired. In the cerebellum, where Fen1 and Lig1 are abundant, the DNA lesion at CAG repeats is correctly repaired: the flappy structure resulting from multinucleotide incorporation by Polβ during long-patch (LP)-BER by Fen1 is efficiently processed, and the subsequent ligation step does not result in expansion. In contrast, in the striatum, where Fen1 and Lig1 proteins are reduced, repair of the DNA lesion at CAG repeats is error-prone. The flappy structure is not efficiently processed, which ultimately leads to repeat expansion through a yet unknown mechanism. Additional DNA repair pathways, including mismatch repair (MMR), might interplay with BER during this process.

Mentions: Moreover, the sequence of the repeat (CAG versus CTG) and the position of the lesion within the CAG/CTG substrates also influenced repair outcome, e.g., repair efficiency and LP-BER requirement [71,72]. The results by Lai et al. suggest that the position of the lesion within the repeat substrate determines whether expansion or contraction occurs [72]. It was reported that a lesion located at the 5'-end of CTG repeats results in expansion, whereas a lesion located in the middle or the 3'-end of the repeats results in deletion. In studies using plasmid-based CAG/CTG substrates and mammalian cell extracts, it was also reported that the position of a nick with respect to the repeat tract influences repair outcome [18,20,22,73]. In these assays, repair efficiency was decreased when the slip-out was located on the CTG strand in comparison to the CAG strand. The mechanism of TNR instability includes both stochastic and deterministic components [74]. The occurrence, accessibility and location of a DNA lesion at repeats are stochastic events that might contribute to the stochastic component of instability, whereas damage repair would be involved in the deterministic component. Since BER protein stoichiometry varies between tissues, this BER deterministic component might be tissue-dependent (Figure 1). Interestingly, the level of MMR proteins, including Msh2, Msh3 and Msh6, is also highly variable between mouse tissues [75]. It was suggested that the elevated levels of MMR proteins in embryonic stem cells of DM1 patients might contribute to the high CTG instability level found in these cells [76]. Similar conclusions were drawn using induced pluripotent stem cells derived from fibroblasts of Friedreich ataxia patients [77,78]. However, the relative levels of MMR proteins were higher in the cerebellum, as compared to the striatum and cortex, indicating that high MMR protein amounts do not correlate with high instability levels in somatic tissues. Further studies are required to specify how tissue-specific regulation of trans-factors impacts on tissue selective instability.


Abnormal base excision repair at trinucleotide repeats associated with diseases: a tissue-selective mechanism.

Goula AV, Merienne K - Genes (Basel) (2013)

Base excision repair (BER)-induced CAG repeat expansion is tissue-dependent. Oxidative DNA lesions, including 8-oxoG lesions, occur stochastically at trinucleotide CAG repeats and are processed by the BER pathway. A DNA glycosylase (e.g., Ogg1) and Ape1 initiate repair. Repair outcome (“no expansion” or “expansion”) is dependent upon the location of the lesion and the tissue that is repaired. In the cerebellum, where Fen1 and Lig1 are abundant, the DNA lesion at CAG repeats is correctly repaired: the flappy structure resulting from multinucleotide incorporation by Polβ during long-patch (LP)-BER by Fen1 is efficiently processed, and the subsequent ligation step does not result in expansion. In contrast, in the striatum, where Fen1 and Lig1 proteins are reduced, repair of the DNA lesion at CAG repeats is error-prone. The flappy structure is not efficiently processed, which ultimately leads to repeat expansion through a yet unknown mechanism. Additional DNA repair pathways, including mismatch repair (MMR), might interplay with BER during this process.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3924826&req=5

genes-04-00375-f001: Base excision repair (BER)-induced CAG repeat expansion is tissue-dependent. Oxidative DNA lesions, including 8-oxoG lesions, occur stochastically at trinucleotide CAG repeats and are processed by the BER pathway. A DNA glycosylase (e.g., Ogg1) and Ape1 initiate repair. Repair outcome (“no expansion” or “expansion”) is dependent upon the location of the lesion and the tissue that is repaired. In the cerebellum, where Fen1 and Lig1 are abundant, the DNA lesion at CAG repeats is correctly repaired: the flappy structure resulting from multinucleotide incorporation by Polβ during long-patch (LP)-BER by Fen1 is efficiently processed, and the subsequent ligation step does not result in expansion. In contrast, in the striatum, where Fen1 and Lig1 proteins are reduced, repair of the DNA lesion at CAG repeats is error-prone. The flappy structure is not efficiently processed, which ultimately leads to repeat expansion through a yet unknown mechanism. Additional DNA repair pathways, including mismatch repair (MMR), might interplay with BER during this process.
Mentions: Moreover, the sequence of the repeat (CAG versus CTG) and the position of the lesion within the CAG/CTG substrates also influenced repair outcome, e.g., repair efficiency and LP-BER requirement [71,72]. The results by Lai et al. suggest that the position of the lesion within the repeat substrate determines whether expansion or contraction occurs [72]. It was reported that a lesion located at the 5'-end of CTG repeats results in expansion, whereas a lesion located in the middle or the 3'-end of the repeats results in deletion. In studies using plasmid-based CAG/CTG substrates and mammalian cell extracts, it was also reported that the position of a nick with respect to the repeat tract influences repair outcome [18,20,22,73]. In these assays, repair efficiency was decreased when the slip-out was located on the CTG strand in comparison to the CAG strand. The mechanism of TNR instability includes both stochastic and deterministic components [74]. The occurrence, accessibility and location of a DNA lesion at repeats are stochastic events that might contribute to the stochastic component of instability, whereas damage repair would be involved in the deterministic component. Since BER protein stoichiometry varies between tissues, this BER deterministic component might be tissue-dependent (Figure 1). Interestingly, the level of MMR proteins, including Msh2, Msh3 and Msh6, is also highly variable between mouse tissues [75]. It was suggested that the elevated levels of MMR proteins in embryonic stem cells of DM1 patients might contribute to the high CTG instability level found in these cells [76]. Similar conclusions were drawn using induced pluripotent stem cells derived from fibroblasts of Friedreich ataxia patients [77,78]. However, the relative levels of MMR proteins were higher in the cerebellum, as compared to the striatum and cortex, indicating that high MMR protein amounts do not correlate with high instability levels in somatic tissues. Further studies are required to specify how tissue-specific regulation of trans-factors impacts on tissue selective instability.

Bottom Line: The mutation is unstable and further expands in specific cells or tissues with time, which can accelerate disease progression.DNA damage and base excision repair (BER) are involved in repeat instability and might contribute to the tissue selectivity of the process.In this review, we will discuss the mechanisms of trinucleotide repeat instability, focusing more specifically on the role of BER.

View Article: PubMed Central - PubMed

Affiliation: Programme of Translational Medicine and Neurogenetics, Institute of Genetics and Molecular and Cellular Biology (IGBMC), UMR 7104-CNRS/INSERM/Uds, 1 rue Laurent Fries, 67404 Illkirch, France. agathi.goula@hotmail.fr.

ABSTRACT
More than fifteen genetic diseases, including Huntington's disease, myotonic dystrophy 1, fragile X syndrome and Friedreich ataxia, are caused by the aberrant expansion of a trinucleotide repeat. The mutation is unstable and further expands in specific cells or tissues with time, which can accelerate disease progression. DNA damage and base excision repair (BER) are involved in repeat instability and might contribute to the tissue selectivity of the process. In this review, we will discuss the mechanisms of trinucleotide repeat instability, focusing more specifically on the role of BER.

No MeSH data available.


Related in: MedlinePlus