Alterations in DNA repair and telomere maintenance mechanism affect response to porphyrins in yeast.
BACKGROUND
DNA quadruplex-interactive porphyrin TMPyP4, but not its isomer TMPyP2, inhibits telomerase activity and causes chromosome fusion in vivo, suggesting interference with telomere maintenance.


METHODS
We examined effects of these porphyrins and hydroxyurea on growth rates of yeast Saccharomyces cerevisiae wild type and strains with defects in telomere maintenance and/or DNA repair pathways (mec1, tel1, rad9), telomere binding protein (cdc13), and anaphase control (pds1).


RESULTS
Hydroxyurea (20 mM) decreased proliferation rates only in mec1 mutant and deletion strains. TMPyP4 (200 microM) decreased growth in all strains, especially in rad9delta and mec1delta. The growth inhibition by TMPyP4 showed low growth inhibition in strains defective in cdc13 and pds1. TMPyP2 sterically prevented from forming a planar species did not significantly inhibit growth of any strain. Overexpression of telomere binding protein Rap1 hypersensitized the mec1delta and tel1delta to TMPyP4.


CONCLUSIONS
Telomere maintenance represents a viable target for anticancer agents.
Izbicka
E
E
Institute for Drug Development, CTRC, San Antonio TX 78245, USA. eizbicka@saci.org
Barnes
L D
LD
Robinson
A K
AK
Davidson
K K
KK
Lawrence
R A
RA
Hannibal
G T
GT
D000970:Antineoplastic Agents / Q000494:pharmacology; D004260:DNA Repair; D004305:Dose-Response Relationship, Drug; D006918:Hydroxyurea / Q000494:pharmacology; D011166:Porphyrins / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D016615:Telomere / Q000378:metabolism*
D000970:Antineoplastic Agents; D011166:Porphyrins; D006918:Hydroxyurea