Mechanisms of Genome Protection and Repair by Unknown

Author:Unknown
Language: eng
Format: epub
ISBN: 9783030412838
Publisher: Springer International Publishing

7.3.3 DNA Repair and Repeat Expansion

Repeat expansion can be detected in tissues with low proliferative activity, such as the brain, oocytes, liver and muscles. For example, oocyte maturation pauses at prophase I of meiosis at the end of embryogenesis, which supports the theory about the non-replicative nature of expansion. In embryonal mouse fibroblasts, a model of MD1, cell cycle blocking at any stage does not block expansion and sometimes increases it (Gomes-Pereira et al. 2014). Thus, some cases of expansion can be explained by alterations in DNA metabolism processes but not in replication. Some proteins from repair and recombination pathways have been shown to function in expansion. It is necessary to emphasize that slipped-strand structures can form during repair and recombination processes. This is due to nascent unusual DNA secondary structures. Currently, a large amount of experimental data has been obtained regarding the involvement of repair in repeat instability. This is the result of many studies using transgenic mouse models.

One group of proteins involved in repair is the mismatch repair (MMR) proteins. This repair mechanism works during DNA replication and recombination. The results confirming the involvement of MMR and replication in repeat instability confirm the complex nature of this phenomenon.

In eukaryotes, one of the main MMR components is MutS heterodimers. The first heterodimer is MutSα, which is composed of MSH2 and MSH6 and participates in MMR. The second component is MutSβ, which is composed of MSH2 and MSH3 and participates in the repair of small insertions or deletions. The MMR machinery functions during replication, where protein complexes required for expansion will have access to secondary structures. The participation of MMR proteins in expansion is supported by experimental evidence, such as secondary structures of CGG/CCG repeats binding MutSα and MutSβ proteins in vitro and in vivo (Zhao et al. 2016). Additionally, MutSβ binds other RED-associated repeats. The MutSα complex promotes expansion indirectly by activating MutSβ. In experiments carried out in mouse models, it was shown that inactivation of MSH2, MSH3 and MSH6 leads to reduced expansion in nondividing cells and reduced repeat instability (Gannon et al. 2012). Research in mouse models of DM1, HD and FXS revealed that MutL proteins and other MMR components are also necessary for expansion. For example, in a HD model, the loss of MutLγ caused the loss of expansion. It is impossible to evaluate the influence of the loss of MutLγ on expansion in the germline because MutLγ(−) mice are sterile. However, it is possible that MutLγ participates in expansion in the germline (Pinto et al. 2013). Additionally, the mouse model showed an effect on the expansion of the Mlh1/Mlh3 complex in the germline (Zhao et al. 2018). Why does MMR promote instability and not prevent it? It is likely that MutS complexes have an affinity for repetitive hairpins. This interaction stabilizes the secondary structure instead of repairing it. However, to date, the mechanism of the MMR effect on expansion has not been sufficiently described. Interestingly, repair of (CTG)20 or (CAG)20 does not require MMR (Hou et al.

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