Delayed repair of radiation induced clustered DNA damage: friend or foe?

Abstract

A signature of ionizing radiation exposure is the induction of DNA clustered damaged sites, defined as two or more lesions within one to two helical turns of DNA by passage of a single radiation track. Clustered damage is made up of double strand breaks (DSB) with associated base lesions or abasic (AP) sites, and non-DSB clusters comprised of base lesions, AP sites and single strand breaks. This review will concentrate on the experimental findings of the processing of non-DSB clustered damaged sites. It has been shown that non-DSB clustered damaged sites compromise the base excision repair pathway leading to the lifetime extension of the lesions within the cluster, compared to isolated lesions, thus the likelihood that the lesions persist to replication and induce mutation is increased. In addition certain non-DSB clustered damaged sites are processed within the cell to form additional DSB. The use of E. coli to demonstrate that clustering of DNA lesions is the major cause of the detrimental consequences of ionizing radiation is also discussed. The delayed repair of non-DSB clustered damaged sites in humans can be seen as a "friend", leading to cell killing in tumour cells or as a "foe", resulting in the formation of mutations and genetic instability in normal tissue.

Fig. 1

Schematic showing DSB and non-DSB clustered DNA damage. DSB can be simple or more complex with associated base lesions and AP sites. Non-DSB clustered damaged, defined as two or more lesions within one or two helical turns of DNA by passage of a single radiation track, increases in complexity with increasing LET of radiation. B, base lesion.

Fig. 2

Schematic to summarise the processing of non-DSB clustered DNA damage. (A) A SSB, induced either directly from ionizing radiation or from cleavage of an AP site, inhibits the repair of an opposing base lesion until it itself has been repaired, thus limiting the formation of DSB. The opposing base lesion, however, impairs the repair of the SSB thus the lifetime of both lesions is increased. If the SSB encounters a replication fork then replication induced DSB could be formed. Increasing the lifetime of the base lesion increases the likelihood the base lesion will be unrepaired at replication and increases the chances of mutation induction. AP, abasic site; B, base lesion; M, mutated base; filled square, incorporated base. (B) Two opposing AP sites are rapidly cleaved to produce a DSB (unless the AP sites are within two bases in the positive direction).

Fig. 3

Schematic to show the induction of a replication induced DSB. If a cluster containing a SSB and a base lesion persists through to replication, both DSB and mutations may be induced. When the replication fork encounters the SSB it collapses, causing replication to stall (replicated strand shown in blue) with the ultimate result of a replication-induced DSB on one of the daughter chromosomes. Replication may bypass the 8-oxoG lesion by adding cytosine or mis-incorporating adenine opposite the 8-oxoG. For faithful repair, 8-oxoG would be removed from the template strand and replaced with guanine. However, if adenine has been wrongly inserted and 8-oxoG is removed before MutYH is able to correct the wrong nucleotide, base pairing will then follow the adenine leading to a fixed GC:TA transversion. Go, 8-oxoG.

Fig. 4

Ionizing radiation can be thought of as a “friend or foe”. If normal tissue is exposed to low doses of radiation (foe) mutations could be induced leading to genetic instability and tumourigenesis. However exposure of tumour tissue to high doses of radiation (friend) can kill the tumour cells. B, base lesion.