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• W2162868052 endingPage "1632" @default.
• W2162868052 startingPage "1618" @default.
• W2162868052 abstract "Myotonic dystrophy type 1 (DM1) is associated with expansion of (CTG)(n) · (CAG)(n) trinucleotide repeats (TNRs) in the 3' untranslated region (UTR) of the DMPK gene. Replication origins are cis-acting elements that potentiate TNR instability; therefore, we mapped replication initiation sites and prereplication complex protein binding within the ~10-kb DMPK/SIX5 locus in non-DM1 and DM1 cells. Two origins, IS(DMPK) and IS(SIX5), flanked the (CTG)(n) · (CAG)(n) TNRs in control cells and in DM1 cells. Orc2 and Mcm4 bound near each of the replication initiation sites, but a dramatic change in (CTG)(n) · (CAG)(n) replication polarity was not correlated with TNR expansion. To test whether (CTG)(n) · (CAG)(n) TNRs are cis-acting elements of instability in human cells, model cell lines were created by integration of cassettes containing the c-myc replication origin and (CTG)(n) · (CAG)(n) TNRs in HeLa cells. Replication forks were slowed by (CTG)(n) · (CAG)(n) TNRs in a length-dependent manner independent of replication polarity, implying that expanded (CTG)(n) · (CAG)(n) TNRs lead to replication stress. Consistent with this prediction, TNR instability increased in the HeLa model cells and DM1 cells upon small interfering RNA (siRNA) knockdown of the fork stabilization protein Claspin, Timeless, or Tipin. These results suggest that aberrant DNA replication and TNR instability are linked in DM1 cells." @default.
• W2162868052 created "2016-06-24" @default.
• W2162868052 creator A5020476156 @default.
• W2162868052 creator A5038982973 @default.
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• W2162868052 creator A5055874515 @default.
• W2162868052 creator A5064973312 @default.
• W2162868052 creator A5088653319 @default.
• W2162868052 date "2012-05-01" @default.
• W2162868052 modified "2023-10-08" @default.
• W2162868052 title "Altered Replication in Human Cells Promotes DMPK (CTG)_<i>n</i> · (CAG)_<i>n</i> Repeat Instability" @default.
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