title: Fen1 does not control somatic hypermutability of the (CTG)(n)*(CAG)(n) repeat in a knock-in mouse model for DM1.
abstract: The mechanism of trinucleotide repeat expansion, an important cause of neuromuscular and neurodegenerative diseases, is poorly understood. We report here on the study of the role of flap endonuclease 1 (Fen1), a structure-specific nuclease with both 5' flap endonuclease and 5'-3' exonuclease activity, in the somatic hypermutability of the (CTG)(n)*(CAG)(n) repeat of the DMPK gene in a mouse model for myotonic dystrophy type 1 (DM1). By intercrossing mice with Fen1 deficiency with transgenics with a DM1 (CTG)(n)*(CAG)(n) repeat (where 104n110), we demonstrate that Fen1 is not essential for faithful maintenance of this repeat in early embryonic cleavage divisions until the blastocyst stage. Additionally, we found that the frequency of somatic DM1 (CTG)(n)*(CAG)(n) repeat instability was essentially unaltered in mice with Fen1 haploinsufficiency up to 1.5 years of age. Based on these findings, we propose that Fen1, despite its role in DNA repair and replication, is not primarily involved in maintaining stability at the DM1 locus.
authors.affiliation: Department of Cell Biology, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Walther J A A
authors.initials: WJ
authors.lastname: van den Broek
authors.forename: Marcel R
authors.initials: MR
authors.lastname: Nelen
authors.forename: Godfried W
authors.initials: GW
authors.lastname: van der Heijden
authors.forename: Derick G
authors.initials: DG
authors.lastname: Wansink
authors.forename: Bé
authors.initials: B
authors.lastname: Wieringa
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001755:Blastocyst / Q000201:enzymology; D004260:DNA Repair / Q000235:genetics*; D004261:DNA Replication / Q000235:genetics*; D004195:Disease Models, Animal; D045585:Flap Endonucleases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009223:Myotonic Dystrophy / Q000201:enzymology / Q000235:genetics*; D040641:Quantitative Trait Loci / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
chemical_list: D045585:Flap Endonucleases