Identification of novel human damage response proteins targeted through yeast orthology.

TitleIdentification of novel human damage response proteins targeted through yeast orthology.
Publication TypeJournal Article
Year of Publication2012
AuthorsSvensson, JP, Fry, RC, Wang, E, Somoza, LA, Samson, LD
JournalPLoS One
Date Published2012
Keywords4-Nitroquinoline-1-oxide, Alkylating Agents, Autophagy, Cell Line, Chromatin Assembly and Disassembly, DNA Damage, DNA Repair, Humans, Methyl Methanesulfonate, Mutagens, Protein Interaction Maps, Quinolones, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Sequence Homology, Amino Acid, tert-Butylhydroperoxide, Vesicular Transport Proteins

Studies in Saccharomyces cerevisiae show that many proteins influence cellular survival upon exposure to DNA damaging agents. We hypothesized that human orthologs of these S. cerevisiae proteins would also be required for cellular survival after treatment with DNA damaging agents. For this purpose, human homologs of S. cerevisiae proteins were identified and mapped onto the human protein-protein interaction network. The resulting human network was highly modular and a series of selection rules were implemented to identify 45 candidates for human toxicity-modulating proteins. The corresponding transcripts were targeted by RNA interference in human cells. The cell lines with depleted target expression were challenged with three DNA damaging agents: the alkylating agents MMS and 4-NQO, and the oxidizing agent t-BuOOH. A comparison of the survival revealed that the majority (74%) of proteins conferred either sensitivity or resistance. The identified human toxicity-modulating proteins represent a variety of biological functions: autophagy, chromatin modifications, RNA and protein metabolism, and telomere maintenance. Further studies revealed that MMS-induced autophagy increase the survival of cells treated with DNA damaging agents. In summary, we show that damage recovery proteins in humans can be identified through homology to S. cerevisiae and that many of the same pathways are represented among the toxicity modulators.

Alternate JournalPLoS ONE
PubMed ID22615993
PubMed Central IDPMC3353887
Grant ListCA112967 / CA / NCI NIH HHS / United States
CA55042 / CA / NCI NIH HHS / United States
ES02109 / ES / NIEHS NIH HHS / United States
P30 ES002109 / ES / NIEHS NIH HHS / United States
R01 CA055042 / CA / NCI NIH HHS / United States