Exp Mol Med.  2002 Sep;34(4):313-317.

Human FEN-1 can process the 5'-flap DNA of CTG/CAG triplet repeat derived from human genetic diseases by length and sequence dependent manner

• Lee SM
• Park MS

Abstract

Trinucleotide repeat (TNR) instability can cause a variety of human genetic diseases including myotonic dystrophy and Huntington's disease. Recent genetic data show that instability of the CAG/CTG repeat DNA is dependent on its length and replication origin. In yeast, the RAD27 (human FEN-1 homologue) null mutant has a high expansion frequency at the TNR loci. We demonstrate here that FEN-1 processes the 5'-flap DNA of CTG/CAG repeats, which is dependent on the length in vitro. FEN-1 protein can cleave the 5'-flap DNA containing triplet repeating sequence up to 21 repeats, but the activity decreases with increasing size of flap above 11 repeats. In addition, FEN-1 processing of 5'-flap DNA depends on sequence, which play a role in the replication origin-dependent TNR instability. Interestingly, FEN-1 can cleave the 5'-flap DNA of CTG repeats better than CAG repeats possibly through the flap-structure. Our biochemical data of FEN-1's activity with triplet repeat DNA clearly shows length dependence, and aids our understanding on the mechanism of TNR instability.

Keyword

trinucleotide repeats; trinucleotide expansion; genetics; neuromuscular direases; DNA replication

MeSH Terms

Base Sequence
DNA, Single-Stranded/*metabolism
Endodeoxyribonucleases/genetics/*metabolism
Flap Endonucleases
Gene Expression Regulation
Genetic Diseases, Inborn/*genetics
Human
Nucleic Acid Conformation
Trinucleotide Repeat Expansion
*Trinucleotide Repeats