RE: Single and double strand DNA breaks

["Carlisle, Sara" <carlisles@aecl.ca>]

Considering the nature of double-strand breaks, one should be more
surprised at the remarkable ability of cells to fix these, rather than
amazed that sometimes the repair process results in genetic change.  The
double-strand break itself, if unrepaired, will prevent successful cell
division, so lack of a repair process would not lead to cancer, the
usual end result we worry about (a cell has to be able to divide if it
is to be malignant!).  

Double-strand breaks are not uniquely formed due to radiation damage,
either - cells have evolved in a hostile chemical environment that
causes a wide variety of classes of damage to DNA, including
double-strand breaks and DNA-DNA or DNA-protein crosslinks, which are
generally repaired by recombinational repair.  Cells are thought to deal
with several double-strand breaks a day, so there has certainly been
plenty of incentive to evolve a mechanism to deal with these
otherwise-lethal damage events.

Recombinational repair of double strand breaks involves finding a piece
of DNA with related information, and using this information as a
template.  Since the second strand of the damaged DNA molecule is also
broken, it cannot act as a source of information.  Most often, the
repair uses the second chromosome copy as a source of information, which
may result in the exchange of some information between the broken
chromosome and the unbroken chromosome.

This is not a problem if both chromosome copies had "normal" genes at
the site of the break point; however, if the second, unbroken chromosome
copy included a defective gene at or near the site, the "normal"
information on the broken chromosome may be replaced by the pre-existing
defective information - and you have "loss of heterozygosity", a major
cause of cancers associated with tumour suppressor genes, for example.
(recall that human cells contain two copies of each chromosome (except
for the sex chromosomes in males); heterozygosity: the two copies of the
same gene on a pair of chromosomes are different; ie: blood groups: one
gene might be "A", the other copy, "B", resulting in the heterozygous
blood type, AB.  Loss of heterozygosity might cause some cells to become
AA, others, BB).

In some cases, the double strand break is repaired using similar
sequence information either at another point on the same chromosome, or
at a point on a different chromosome.  Repair of this type may lead to
insertion or deletion mutations, or translocations, which have their own
problems, including in some cases leading to increased cancer risk.

If I have managed to lose everyone through use of too much biological
jargon, I'd be happy to give this another try!  Hope I've been of some
help


Sara M. Carlisle
Radiation Biology and Health Physics Branch
AECL, Chalk River Laboratories
Chalk River, ON K0J 1J0
Canada

phone (613) 584-8811 extn 3667
fax        (613) 584-1713
email   carlisles@aecl.ca