Altered replication in human cells promotes DMPK (CTG)(n) · (CAG)(n) repeat instability.

Molecular and Cellular Biology
Guoqi LiuMichael Leffak

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) ...Continue Reading

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Citations

May 10, 2013·Nucleic Acids Research·Xiaomi ChenMichael Leffak
Apr 14, 2016·Current Genetics·Mariana C GadaletaEishi Noguchi
May 15, 2016·Nucleic Acids Research·Joanna BarthelemyMichael Leffak
Dec 6, 2016·Nature Structural & Molecular Biology·Jane C KimSergei M Mirkin
Mar 5, 2017·American Journal of Human Genetics·Lise BarbéChristopher E Pearson
Jun 18, 2017·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Michael Leffak
Nov 27, 2018·Nucleic Acids Research·Lionel GellonCatherine H Freudenreich
Aug 1, 2018·Nature Structural & Molecular Biology·Artem V KononenkoSergei M Mirkin
Jan 16, 2013·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Andrei Kuzminov
Sep 3, 2020·The Journal of Biological Chemistry·Rujuta Yashodhan GadgilMichael Leffak
Feb 14, 2021·Journal of Huntington's Disease·Vanessa C Wheeler, Vincent Dion
Mar 24, 2018·Trends in Genetics : TIG·Ryan J McGinty, Sergei M Mirkin

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