| Altered replication in human cells promotes DMPK (CTG)(n) · (CAG)(n) repeat instability. | |
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MedLine Citation:
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PMID: 22354993 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Guoqi Liu; Xiaomi Chen; Yanzhe Gao; Todd Lewis; Joanna Barthelemy; Michael Leffak |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2012-02-21 |
Journal Detail:
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Title: Molecular and cellular biology Volume: 32 ISSN: 1098-5549 ISO Abbreviation: Mol. Cell. Biol. Publication Date: 2012 May |
Date Detail:
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Created Date: 2012-04-11 Completed Date: 2012-06-25 Revised Date: 2013-02-19 |
Medline Journal Info:
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Nlm Unique ID: 8109087 Medline TA: Mol Cell Biol Country: United States |
Other Details:
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Languages: eng Pagination: 1618-32 Citation Subset: IM |
Affiliation:
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Department of Biochemistry and Molecular Biology, Boonshoft School of Medicine, Wright State University, Dayton, Ohio, USA. guoqi.liu@yahoo.com |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Cell Line Chromosomal Instability DNA / metabolism* DNA Replication* Humans Protein-Serine-Threonine Kinases / genetics* Trinucleotide Repeats* |
| Grant Support | |
ID/Acronym/Agency:
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GM53819/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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9007-49-2/DNA; EC 2.7.1.-/myotonic dystrophy protein kinase; EC 2.7.11.1/Protein-Serine-Threonine Kinases |
| Comments/Corrections | |
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