Authors: Bacolla, A, Bowater, RP, Gellibolian, R, Iyer, RR, Jakupciak, J,
Jaworski, A, Larson, JE, Ohshima, K, Parniewski, P, Pluciennik, A, Wells,
RD.

Institutions: Institute of Biosciences and Technology, Texas A&M University
System Health Science Center, 2121 W. Holcombe Blvd., Houston, TX
77030-3303, USA

The nucleic acid molecular mechanisms responsible for genetic
instabilities of CTG*CAG repeat sequences involved in the etiology of
myotonic dystrophy is investigated. Expansions and deletions in this
triplet repeat sequence (TRS) are mediated by DNA replication and tandem
duplication, repair, recombination-gene conversion, or a composite of these
mechanisms acting in concert. The slippage of the complementary strands of
the repeat sequences to form hairpin loop structures, or slipped
conformations, with differing relative stabilities are important components
in the mechanism. The inherent conformational properties of these
sequences, such as their high degree of flexibility, writhing, and stability
of hairpin formation, facilitates the strand slippage. The unusual DNA
conformations cause DNA polymerase stalling and hairpin formation,
exacerbating the disease-causing mutagenesis. Several genetic/biochemical
factors are involved including methyl-directed mismatch repair, nucleotide
excision repair, single-strand DNA binding protein, transcription, and DNA
polymerase III proofreading.

The recent emphasis of our laboratory stems from the discovery that
genetic recombination is a robust mechanism for expanding CTG*CAG repeats.
Gene conversion (recombinational repair) is, by far, the most powerful
expansion mechanism compared to replication, repair, and tandem
duplications. Thus, gene conversion may be the expansion mechanism for
myotonic dystrophy.