Absence of MutSß leads to the formation of slipped-DNA for CTG/CAG contractions at primate replication forks.
DNA Repair (Amst)
; 42: 107-18, 2016 06.
Article
em En
| MEDLINE
| ID: mdl-27155933
ABSTRACT
Typically disease-causing CAG/CTG repeats expand, but rare affected families can display high levels of contraction of the expanded repeat amongst offspring. Understanding instability is important since arresting expansions or enhancing contractions could be clinically beneficial. The MutSß mismatch repair complex is required for CAG/CTG expansions in mice and patients. Oddly, by unknown mechanisms MutSß-deficient mice incur contractions instead of expansions. Replication using CTG or CAG as the lagging strand template is known to cause contractions or expansions respectively; however, the interplay between replication and repair leading to this instability remains unclear. Towards understanding how repeat contractions may arise, we performed in vitro SV40-mediated replication of repeat-containing plasmids in the presence or absence of mismatch repair. Specifically, we separated repair from replication Replication mediated by MutSß- and MutSα-deficient human cells or cell extracts produced slipped-DNA heteroduplexes in the contraction- but not expansion-biased replication direction. Replication in the presence of MutSß disfavoured the retention of replication products harbouring slipped-DNA heteroduplexes. Post-replication repair of slipped-DNAs by MutSß-proficient extracts eliminated slipped-DNAs. Thus, a MutSß-deficiency likely enhances repeat contractions because MutSß protects against contractions by repairing template strand slip-outs. Replication deficient in LigaseI or PCNA-interaction mutant LigaseI revealed slipped-DNA formation at lagging strands. Our results reveal that distinct mechanisms lead to expansions or contractions and support inhibition of MutSß as a therapeutic strategy to enhance the contraction of expanded repeats.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
DNA
/
Expansão das Repetições de Trinucleotídeos
/
Replicação do DNA
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Proteína MutS de Ligação de DNA com Erro de Pareamento
Limite:
Animals
/
Humans
Idioma:
En
Revista:
DNA Repair (Amst)
Assunto da revista:
BIOLOGIA MOLECULAR
/
BIOQUIMICA
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Canadá