myotonic dystrophy - IDMC.org

Abstract No : 10
ORAL PRESENTATIONS
LONG DM1 AND DM2 REPEAT SEQUENCES INDUCE GROSS
REARRANGEMENTS IN FLANKING DNA SEQUENCES
Wojechowska M., Bacolla A., Dere R., Hebert M., Kosmider B., Larson J. E.,
Napierala M., Son L.S. and Wells R.D.
Institute of Biosciences and Technology, Texas A&M University System Health Science Center,
2121 W. Holcombe Blvd., Houston, TX 77030-3303, USA
The molecular mechanisms responsible for the genetic instabilities (expansions and contractions)
of repeating tri- and tetranucleotide tracts, which are involved in the etiology
of certain neurological diseases, are under investigation. Replication, recombination,
and several repair mechanisms (including the involvement of DSBs) have been implicated
in the bacterial and mammalian cell studies. We have recently discovered that long
tracts of CTG/CAG, CCTG/CAGG, or CGG/CCG repeats cause complex rearrangements,
including inversions and gross deletions, spanning several Kbp of flanking sequences.
Investigations in E. coli, COS-7, and HEK-293 cells show that longer tracts (full mutations)
are most potent, and the orientation of the repeats and their transcriptional status
influence the mutagenic potential as well as the types of products. The locations of
the breakpoints coincided with structurally contorted regions of the putative non-B DNA
conformations (cruciforms, slipped structures, triplexes, tetraplexes) in these sequences.
The consequences of these discoveries for DM1 and DM2 patients with full mutations
remain to be elucidated but may have profound implications for the integrity of their
gene products. (Supported by N.I.H, Robert A. Welch Foundation, Friedreich’s Ataxia
Research Alliance, and Muscular Dystrophy Association.)
QUEBEC 2005 31