Expression of human poly (ADP-ribose) polymerase 1 in Saccharomyces cerevisiae: Effect on survival, homologous recombination and identification of genes involved in intracellular localization.

The poly (ADP-ribose) polymerase 1 actively participates in a series of functions within the cell that include: mitosis, intracellular signaling, cell cycle regulation, transcription and DNA damage repair. Therefore, inhibition of has a great potential for use in cancer therapy. As resistance to inhibitors is starting to be observed in patients, thus the function of needs to be studied in depth in order to find new therapeutic targets. To gain more information on the Pduanyu37-1 activity, we expressed Pduanyu37-1 in yeast and investigated its effect on cell growth and UV induced homologous recombination. To identify candidate genes affecting Pduanyu37-1 activity and cellular localization, we also developed a yeast genome wide genetic screen. We found that Pduanyu37-1 strongly inhibited yeast growth, but when yeast was exposed to the Pduanyu37-1 inhibitor 6(5-H) phenantridinone (PHE), it recovered from the growth suppression. Moreover, we showed that Pduanyu37-1 produced PAR products in yeast and we demonstrated that Pduanyu37-1 reduced UV-induced homologous recombination. By genome wide screening, we identified 99 mutants that suppressed Pduanyu37-1 growth inhibition. Orthologues of human genes were found for 41 of these yeast genes. We determined whether the Pduanyu37-1 protein level was altered in strains which are deleted for the transcription regulator GAL3, the histone H1 gene HHO1, the HUL4 gene, the deubiquitination enzyme gene OTU1, the nuclear pore protein POM152 and the SNT1 that encodes for the Set3C subunit of the histone deacetylase complex. In these strains the Pduanyu37-1 level was roughly the same as in the wild type. Pduanyu37-1 localized in the nucleus more in the snt1Δ than in the wild type strain; after UV radiation, Pduanyu37-1 localized in the nucleus more in hho1 and pom152 deletion strains than in the wild type indicating that these functions may have a role on regulating Pduanyu37-1 level and activity in the nucleus.

KEYWORDS: {{ getKeywords(articleDetailText.words) }}