title: Identification of a Mitochondrial DNA Polymerase Affecting Cardiotoxicity of Sunitinib Using a Genome-Wide Screening on S. pombe Deletion Library.
abstract: Drug toxicity is a key issue for drug R&D, a fundamental challenge of which is to screen for the targets genome-wide. The anticancer tyrosine kinase inhibitor sunitinib is known to induce cardiotoxicity. Here, to understand the molecular insights of cardiotoxicity by sunitinib at the genome level, we used a genome-wide drug target screening technology (GPScreen) that measures drug-induced haploinsufficiency (DIH) in the fission yeast Schizosaccharomyces pombe genome-wide deletion library and found a mitochondrial DNA polymerase (POG1). In the results, sunitinib induced more severe cytotoxicity and mitochondrial damage in POG1-deleted heterozygous mutants compared to wild type (WT) of S. pombe. Furthermore, knockdown of the human ortholog POLG of S. pombe POG1 in human cells significantly increased the cytotoxicity of sunitinib. Notably, sunitinib dramatically decreased the levels of POLG mRNAs and proteins, of which downregulation was already known to induce mitochondrial damage of cardiomyocytes, causing cardiotoxicity. These results indicate that POLG might play a crucial role in mitochondrial damage as a gene of which expressional pathway is targeted by sunitinib for cardiotoxicity, and that genome-wide drug target screening with GPScreen can be applied to drug toxicity target discovery to understand the molecular insights regarding drug toxicity.
authors.affiliation: GPScreen Team, Bioneer Corporation, Daejeon 306-220, Republic of Korea dmkima@bioneer.co.kr.
authors.forename: Dong-Myung
authors.initials: DM
authors.lastname: Kim
authors.affiliation: GPScreen Team, Bioneer Corporation, Daejeon 306-220, Republic of Korea.
authors.forename: Hanna
authors.initials: H
authors.lastname: Kim
authors.affiliation: GPScreen Team, Bioneer Corporation, Daejeon 306-220, Republic of Korea.
authors.forename: Ji-Hyun
authors.initials: JH
authors.lastname: Yeon
authors.affiliation: GPScreen Team, Bioneer Corporation, Daejeon 306-220, Republic of Korea.
authors.forename: Ju-Hee
authors.initials: JH
authors.lastname: Lee
authors.affiliation: GPScreen Team, Bioneer Corporation, Daejeon 306-220, Republic of Korea.
authors.forename: Han-Oh
authors.initials: HO
authors.lastname: Park
mesh_terms: D000970:Antineoplastic Agents / Q000633:toxicity*; D066126:Cardiotoxicity / Q000209:etiology; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000502:physiology*; D055106:Genome-Wide Association Study; D015698:Genomic Library; D006367:HeLa Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D007211:Indoles / Q000633:toxicity*; D008928:Mitochondria / Q000187:drug effects; D011758:Pyrroles / Q000633:toxicity*; D012568:Schizosaccharomyces / Q000187:drug effects* / Q000235:genetics; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics; D017384:Sequence Deletion; D000077210:Sunitinib
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D029702:Schizosaccharomyces pombe Proteins; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human; D000077210:Sunitinib
keywords: drug-induced cardiotoxicity; genome-wide drug target screening; mitochondrial damages; sunitinib