Trinucleotide repeat (TNR) instability can cause avariety of human genetic diseases including myo-tonic dystrophy and Huntington 's disease. Recentgenetic data show that instability of the CAG/CTGrepeat DNA is dependent on its length and replica-tion ...
Trinucleotide repeat (TNR) instability can cause avariety of human genetic diseases including myo-tonic dystrophy and Huntington 's disease. Recentgenetic data show that instability of the CAG/CTGrepeat DNA is dependent on its length and replica-tion origin. In yeast, the RAD27 (human FEN-1 homo-logue) null mutant has a high expansion frequency atthe TNR loci. We demonstrate here that FEN-1 pro-cesses the 5 '-flap DNA of CTG/CAG repeats, whichis dependent on the length in vitro. FEN-1 proteincan cleave the 5 '-flap DNA containing triplet repeat-ing sequence up to 21 repeats, but the activitydecreases with increasing size of flap above 11repeats. In addition, FEN-1 processing of 5 '-flap DNAdepends on sequence, which play a role in the repli-cation origin-dependent TNR instability. Interestingly,FEN-1 can cleave the 5 '-flap DNA of CTG repeats bet-ter than CAG repeats possibly through the flap-struc-ture. Our biochemical data of FEN-1 's activity withtriplet repeat DNA clearly shows length dependence,and aids our understanding on the mechanism ofTNR instability.