Can a mixed damage interfere with DNA‐prottein cross‐links repair?

Abstract

Studying the damage induced into DNA by furocoumarin sensitization, particularly covalent DNA-protein cross-links (DPC), we have observed that an angelicin isoster, namely 1,4,6,8-tetramethyl-2H-furo[2,3-h]quinolin-2-one (FQ), can selectively induce DPC [1,2] when used by means of the wellknown method called double irradiation. This method was introduced studying furocoumarin interstrands cross-links (ISC), which are formed by a biphotonic reaction [3]. According to this protocol, after a first irradiation step, during which the sensitizer mainly induces DNA monoadducts (MA), the unbound furocoumarin molecules are washed out and the system irradiated again. MA can further react with another DNA base, yielding biadducts, i.e., ISC. Therefore, using the double irradiation protocol furocoumarins can induce ISC but no additional MA; thus, it becomes possible to select the biological effects of ISC. We have observed that also FQ forms biadducts between DNA and proteins by a biphotonic mechanism, but, unlike linear furocou-J. Cell.Mol.Med. Vol 5, No 2, 2001 pp. 171-177 Abstract Some photochemical and photobiological properties of 4,5',8-trimethylpsoralen (TMP) have been studied in comparison with 1,4,6,8-tetramethyl-2H-furo[2,3-h]quinolin-2 one (FQ) and 8-methoxypsoralen (8-MOP). TMP and FQ can photobind to mammalian cell DNA in vivo, by UVA irradiation, forming DNA-protein cross-links (DPC), but only TMP shows a strong capacity of inducing interstrand cross-links (ISC).The mechanism of DPC formation was studied using the double irradiation method in Chinese hamster ovary (CHO) cells, and DPC were detected by alkaline elution. Both TMP and FQ induce covalent diadducts linking together DNA and proteins. Studying the formation of double strand breaks (DSB) in CHO cells we observed that TMP induced a low amount of DSB, similar to 8-MOP. TMP and 8-MOP induced chromosomal aberrations in CHO cells to the same extent, while FQ appeared to be more active. Our data suggest that the ISC induced by TMP could trap enzymes involved in DPC repair.

T4 Phage Photoinactivation by Linear Furocoumarins and Angular Furoquinolinones

“…The authors concluded that during the second irradiation step (when bifunctional adducts are selectively formed), some lethal lesions other than ISCs are formed. Because, as mentioned above, TMP17 and 8‐MOP7, 16 can efficiently induce DPCs by a two‐step photoreaction, we can speculate that these lesions could be DPCs.…”

“…2, 6 Alternatively, this second reaction can involve a protein to form a DPC 7. 16 All three derivatives chosen can form various MAs in DNA, but TMP is known to be capable of inducing numerous ISCs13, 14 and DPCs17 as well. FQ and HFQ efficiently form DPCs, but not ISCs,15, 16 a behavior common to all furocoumarins with an angular molecular structure.…”