International Journal of Radiation Biology , 75: 657-752, 1999
Clustering of radiation-produced breaks along chromosomes:
modeling the effects on chromosome aberrations
R.K. SACHS, A.M. CHEN, P.J. SIMPSON**,
L.R. HLATKY*, P. HAHNFELDT*, and J.R.K. SAVAGE**
Dept. Math., University of California, Berkeley, CA 94720.
**MRC Radiation and Genome Stability Unit, Harwell, Didcot, OX11
0RD, UK. *DFCI, Harvard University, Boston, MA 02215.
Abstract. Purpose. For high LET radiations, and perhaps even for
hard x-rays, DSBs (DNA double strand breaks) are clustered
non-randomly along chromosomes; disproportionately many inter-DSB
segments are less than a few Mbp. We analyze the implications of
such DSB clustering for chromosome aberrations.
Methods. Chromosome segments between different DSBs within
one DSB cluster are assumed too small to detect in the aberration
assay. Enumeration or Monte-Carlo computer simulations are used
to compute relative frequencies of many observable aberration
patterns, apparently simple or visibly complex.
The theoretical predictions are
compared with x-ray data for human fibroblasts, involving painted
chromosomes 1, 2, 4, 5, 7 or 13.
Results and Conclusions. Surprisingly, cryptic DSB
multiplicity does not affect the frequency ratios predicted for
aberration patterns by a random breakage-and-rejoining model. The
model is generally consistent with current data on many different
types of aberrations, whether or not DSBs usually occur in
cryptic clusters. For a Revell-type exchange model, however, the
predictions do depend on clustering configurations; they gradually
approach the predictions of the breakage-and-rejoining model as
average cluster multiplicity increases. The model is consistent
with the data, e.g. with the ratio of visibly complex to
apparently simple aberrations, only if there is considerable DSB
clustering even at low LET, with ~1.5 or more reactive DSBs per
cluster on average.
Running head: DSB clusters and chromosome aberrations
Indexing Phrases. ionizing radiation; DNA double strand
break clustering; chromosome aberration models; computer
simulations.
Clusters