Nucleic Acids Research, Vol 26, Issue 8 1980-1984, Copyright © 1998 by Oxford University Press
M Nakayabu, S Miwa, M Suzuki, S Izuta, G Sobue and S Yoshida
We have studied the contribution of mismatch sequences to the trinucleotide
repeat expansion that causes hereditary diseases. Using an oligonucleotide
duplex, (CAG)5/(CTG)5, as a template-primer, DNA synthesis was carried out
using either Escherichia coli DNA polymerase I (Klenow fragment) or human
immunodeficiency virus type I reverse transcriptase (HIV-RT). Both enzymes
expanded the repeat sequence longer than 27 nucleotides (nt), beyond the
maximum length expected from the template size. The expansion was observed
under conditions in which extension occurs either in both strands or in one
strand. In contrast, with another template-primer that contains a
non-repetitive flanking sequence 5'-upstream of the repetitive sequence,
the reaction products were not extended beyond the template size (45 nt) by
these DNA polymerases. We then used mismatched template-primers, in which
either 1, 2 or 6 non-complementary nucleotides were introduced to the
repeat sequence that is flanked by a non-repetitive sequence. In this case,
primers were efficiently expanded over the expected length of 45 nt, in a
mismatch-dependent manner. One of the primers with six mismatches extended
as long as 72 nt. These results imply that the misincorporation of
non-complementary deoxyribonucleoside monophosphates (dNMPs) into the
repeat sequence makes double-stranded DNA unstable and triggers the
slippage and expansion of trinucleotide repeats by forming loops or hairpin
structures during DNA synthesis.
ARTICLES
Mismatched nucleotides may facilitate expansion of trinucleotide repeats in genetic diseases
Department of Neurology and Laboratory of Cancer Cell Biology, Institute of Disease Mechanism and Control, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
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