LIFE01200604005 Shri Somnath Ghosh - Homi Bhabha National ...

CHAPTER 1
INTRODUCTION
unrepaired damage is a block to replication as is the case for thymidine glycol or an AP
site. Homologous recombination or single strand annealing will overcome the collapse of
the replication fork and may produce deletions. Importantly, the cell will survive with
mutations or loss of genetic material. The more complex the non-DSB cluster (i.e. several
oxidized base damages or SSB/gap), the more complex the subsequent mutations. The
presence of two or more base substitutions or ±1 insertions/deletions can be considered
the signature of complex non-DSB clusters. The repair of complex DSBs, either formed
by the radiation track or originating from “repair” of non-DSB clusters, is likely
compromised and very slow, potentially forming large deletions. Lethal events may be
expected from such lesions, even though this has not yet been demonstrated.
Fig.1.5. Biological consequences of clustered DNA damage in eukaryotes. Clustered damage in
the form of non-DSB bistranded lesions, tandem lesions or complex DSBs can consist of AP sites
(A), SSBs or base damage (O is 8-oxoG, fU is 5-formyluracil, hU is 5-hydroxyuracil, and FA is
formylamine). Two opposing AP sites can be converted to a DSB and hence complex DSBs can
be formed either directly by the DNA damaging agent or by abortive BER. Complex DSBs can
decrease the efficiency of NHEJ and be inaccurately repaired. Lesions of high complexity can
result in mutagenesis: DSBs are not formed due to inhibition of repair enzymes by near-by
damage. Tandem lesions can block DNA replication, but can also be mutagenic as found for
bistranded lesions consisting of base damage. Partial processing of these latter two types of
lesions could also result in persistent SSBs. Clustered lesions can therefore be mutagenic, result
in DSBs and inaccurate repair, or block replication, and could be cytotoxic to the eukaryote cell.
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