Re: DNA damage from low-LET radiation

["Björn Cedervall" <bjorn_cedervall@hotmail.com>]

>I recently read a letter by John Wards in Radiation Research (1991)
>discussing qualitative differences in DNA damage caused by radiation 

Low-LET such as "X-rays" causes DSBs - typically about
.005 DSB per Gy and Mbp in mammalian cells (Mbp=Million
DNA base pairs, for a comparison: Recent estimates (PNAS
1991) a human chromosome has an average size of 143 Mbp).

A major difference between high- and low-LET is that
the high-LET radiation produces much more severe
lesions (difficult to repair) than low-LET radiation.
By the definition of LET - the distribution of ionization 
events differs largely within a cell nucleus.
There are still many unknown details regarding the
underlying mechanisms: A low-LET induced lesion can
definitely also be very complex from an organic chemical
point of view and it is possible that even a single
ionization cluster may cause _double_ DNA double strand (DSB)
breaks within the same strand - resulting in large deletions
of DNA (perhaps corresponding to complete DNA loops with
the two DSBs close to the loop attachment sites. Nevertheless,
the cell repair machinery is probably still able to repair
(replace) _most_ such lost pieces of DNA (by using the
homologous "backup" chromosome).
It has not been clarified what the characteristics are of the
critical targets (it is not even clear if it is only DNA – it may
be DNA-protein complexes or say DNA-nuclear membrane
structures. The latter possibilities have not been excluded.
I wouldn't be surprised if there are a few different types of
Critical targets/types of lesions.

Then the question is what high-LET is doing that low-LET doesn't
do (or does but with a lower probability per Gy). There are
a lot of speculations about the lesion character but a bottom
line must be that they are much more difficult to repair correctly
compared to those lesions caused by low-LET radiation. Well,
those were my immediate reflections. Papers that you may want
to look at are a few regarding DNA loop breaks that were published
in Radiat. Res. about a year ago. There are also many excellent
papers on the distribution of ionization clusters by prof. Goodhead
in England. Please comment or suggest further readings.

bjorn_cedervall@hotmail.com,
Assoc. Prof., Medical Radiation Biology, 
Karolinska Institutet, Box 260, S-171 76 Stockholm, Sweden 
Fax: Int + 468 343525
Any opinions expressed above are those of mine and may not 
necessarily coincide with those of others. 



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