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J Biol Chem, Vol. 274, Issue 37, 25975-25978, September 10, 1999
From the Lineberger Comprehensive Cancer Center and Department of
Pathology, University of North Carolina Medical School, Chapel
Hill, North Carolina 27599-7295
The occurrence of triplet-repeat expansion (TRE)
during transmission of genetic information is involved in many
neurological and neuromuscular diseases including Fragile X syndrome
and myotonic dystrophy. DNA slippage during replicative synthesis
appears to cause TRE. The causes of DNA slippage, however, remain
mostly unknown. We investigated the effects of abasic sites on the
occurrence of TRE during DNA replication in vitro using
Escherichia coli Klenow polymerase I as the model
polymerase. Here we show that a single abasic site analog, synthesized
in the triplet-repeat tract at the 5' end of the template strand,
induced dramatic TRE during DNA synthesis. The amount of TRE induced
decreased when the abasic site was moved to the middle of the repeat
tract, consistent with effectively decreasing the length of the repeat
tract. Placing the abasic site in the primer did not induce TRE. TRE
was sequence-dependent. The damage-induced increase in
growing strand TRE depended on the sequence of the growing strand
repeat as AAT ~ ATT > CAG > CTG. The expansions
required replication from a primer complementary to the repeat tract.
The expanded tracts were sequenced and contained multiple additions of
the original repeat. The results imply that DNA damage can play a
significant role in generating TRE in vivo.
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