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Z-DNA-forming sequences generate
large-scale deletions in mammalian cells
Guliang Wang, Laura A.
Christensen, and Karen M. Vasquez *
Department of Carcinogenesis,
University of Texas M. D. Anderson Cancer Center, Science
Park-Research Division, 1808 Park Road 1-C, Smithville, TX 78957.
Communicated by Philip C. Hanawalt, Stanford University, Stanford,
CA, December 23, 2005 (received for review August 31, 2005).
Spontaneous chromosomal
breakages frequently occur at genomic hot spots in the
absence of DNA damage and can result in translocation-related human
disease.
Chromosomal breakpoints are often mapped near purine-pyrimidine
Z-DNA-forming sequences in human tumors.
However, it is not known whether Z-DNA plays a role in the
generation of these chromosomal breakages.
Here, we show that Z-DNA-forming sequences induce high
levels of genetic instability in both bacterial and
mammalian cells.
In mammalian cells, the Z-DNA-forming sequences induce
double-strand breaks nearby, resulting in large-scale deletions
in 95% of the mutants.
These Z-DNA-induced double-strand breaks in mammalian cells
are not confined to a specific sequence but rather are
dispersed over a 400-bp region, consistent with chromosomal
breakpoints in human diseases.
This observation is in contrast to the mutations generated
in Escherichia coli that are predominantly
small deletions within the repeats.
We found that the frequency of small deletions is increased
by replication in mammalian cell extracts.
Surprisingly, the large-scale deletions generated in
mammalian cells are, at least in part, replication-independent
and are likely initiated by repair processing cleavages
surrounding the Z-DNA-forming sequence.
These results reveal that mammalian cells process
Z-DNA-forming sequences in a strikingly different fashion
from that used by bacteria.
Our data suggest that Z-DNA-forming sequences may be causative factors
for gene translocations found in leukemias and lymphomas and
that certain cellular conditions such as active transcription may
increase the risk of Z-DNA-related genetic instability.
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Author contributions: G.W. and K.M.V.
designed research; G.W. and L.A.C. performed research; G.W. and K.M.V.
analyzed data; and G.W. and K.M.V. wrote the paper.
Conflict of interest statement: No conflicts declared.
*To whom correspondence should be addressed at: Department
of Carcinogenesis, University of Texas M. D. Anderson Cancer Center,
1808 Park Road 1-C, P.O. Box 389, Smithville, TX 78957.
Karen M. Vasquez, E-mail: kvasquez@sprd1.mdacc.tmc.edu
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