Recent Advances in Psoralen Phototoxicity Mechanism

Averbeck, D.

doi:10.1111/j.1751-1097.1989.tb02917.x

Cited by 219 publications

(120 citation statements)

References 254 publications

(212 reference statements)

Supporting

Mentioning

114

Contrasting

Unclassified

Order By: Relevance

“…Psoralen photoreaction of replicating yeast cells induces NER-dependent DNA breaks; monoadducts induce single-strand nicks, whereas interstrand cross-links induce DSBs (2,5,(17)(18)(19)(20). Rejoining of the cross-link-induced DSBs depends on the HR genes RAD51 and RAD52 (2,5,(21)(22)(23). These observations suggest the following two-step model for psoralen cross-link repair; 1) NER acts on cross-links to produce DSBs, and 2) the DSBs are repaired by HR.…”

mentioning

confidence: 86%

DNA Repair Defects Channel Interstrand DNA Cross-links into Alternate Recombinational and Error-prone Repair Pathways

Saffran

Ahmed

Bellevue

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

The repair of psoralen interstrand cross-links in the yeast Saccharomyces cerevisiae involves the DNA repair groups nucleotide excision repair (NER), homologous recombination (HR), and post-replication repair (PRR). In repair-proficient yeast cells cross-links induce double-strand breaks, in an NER-dependent process; the double-strand breaks are then repaired by HR. An alternate error-prone repair pathway generates mutations at cross-link sites. We have characterized the repair of plasmid molecules carrying a single psoralen cross-link, psoralen monoadduct, or double-strand break in yeast cells with deficiencies in NER, HR, or PRR genes, measuring the repair efficiencies and the levels of gene conversions, crossing over, and mutations. Strains with deficiencies in the NER genes RAD1, RAD3, RAD4, and RAD10 had low levels of cross-link-induced recombination but higher mutation frequencies than repair-proficient cells. Deletion of the HR genes RAD51, RAD52, RAD54, RAD55, and RAD57 also decreased induced recombination and increased mutation frequencies above those of NER-deficient yeast. Strains lacking the PRR genes RAD5, RAD6, and RAD18 did not have any crosslink-induced mutations but showed increased levels of recombination; rad5 and rad6 cells also had altered patterns of cross-link-induced gene conversion in comparison with repair-proficient yeast. Our observations suggest that psoralen cross-links can be repaired by three pathways: an error-free recombinational pathway requiring NER and HR and two PRR-dependent errorprone pathways, one NER-dependent and one NERindependent.DNA interstrand cross-links are complex lesions, highly toxic to cells, and difficult to repair because of the involvement of both strands of the DNA duplex. A single unrepaired interstrand cross-link is sufficient to kill a cell, and multiple DNA repair pathways may be required to complete cross-link removal (1-7).The yeast Saccharomyces cerevisiae has three major DNA repair epistasis groups, all of which are involved in cross-link repair; they are nucleotide excision repair, recombinational repair, and post-replication repair (8). Nucleotide excision repair (NER) 1 is a general system that recognizes bulky and helix-distorting lesions (9, 10). Endonucleases nick the affected DNA strand on both the 5Ј and 3Ј sides of the lesion; after removal of the damaged oligonucleotide, the resulting singlestrand gap is filled in by polymerase activity using the undamaged strand as a template. This mechanism produces error-free repair of single-strand damage. Recombinational repair is the major pathway for repair of double-strand damage, such as double-strand breaks (DSBs) or gaps in yeast (11,12). In homologous recombination (HR) the broken DNA molecule is repaired, and missing genetic information is restored through interactions with intact homologous sequences. This pathway is also non-mutagenic but can result in DNA rearrangements. Post-replication repair (PRR) acts on damage in the context of DNA replication, allowing for bypass of replication fork-...

show abstract

mentioning

confidence: 86%

DNA Repair Defects Channel Interstrand DNA Cross-links into Alternate Recombinational and Error-prone Repair Pathways

Saffran

Ahmed

Bellevue

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…To determine whether PAP-1 can be safely used in vivo we performed several general toxicity studies and put PAP-1 through an industrial type "Lead Profiling Screen" for selectivity over a panel of 56 receptors. We also more specifically tested for inhibition of P450-dependent enzymes and for photoxicity because some psoralens have been reported to exhibit these properties (Averbeck, 1989;Zhang et al, 2001).…”

Section: Probing Of the Alkoxypsoralen Pharmacophore Tomentioning

confidence: 99%

Design of PAP-1, a Selective Small Molecule Kv1.3 Blocker, for the Suppression of Effector Memory T Cells in Autoimmune Diseases

et al. 2005

View full text Add to dashboard Cite

show abstract

“…Nishio, Y., T. Kakizoe, M. Ohtani, S. Sato, T. Sugimura and S. (1)(2)(3)(4)(5)(6)(7). Although many phototoxic compounds are photomutagenic, others, such as retinoids and nitro-benzodiazepines are not photomutagenic (8,9).…”

mentioning

confidence: 99%