title: Two fission yeast high mobility group box proteins in the maintenance of genomic integrity following doxorubicin insult.
abstract: Drug resistance is a challenge in chemotherapy, and, to date, there has been little resolution as to how it is induced. We previously isolated a host of doxorubicin resistance (DXR) genes in fission yeast and here we investigate the regulation of this resistance through two high mobility group (HMG) motif-containing DXR proteins, Nht1 and Hap2. The concurrent deletion of nht1 and hap2 did not confer cumulative sensitivity to doxorubicin, indicating that these factors cooperate closely in similar epistatic groups. We show that doxorubicin treatment resulted in the subcellular reorganization of Rhp54, a homologous recombination-dependent DNA damage repair protein. The disruption of either nht1 or hap2 attenuated Rhp54-foci formation, suggesting that these factors modulate the repair of doxorubicin-induced DNA lesions via the recruitment of homologous recombination machinery. Epistatic analyses further confirmed that Nht1 and Hap2 act in similar functional groups with complexes related to DSB repair but act synergistically with factors that regulate transcription and chromosome segregation. Overall, this work shows the molecular crosstalk coordinated by HMG proteins in conferring doxorubicin resistance in fission yeast.
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; National University Health System (NUHS), Singapore.
authors.forename: Ming Yi Richard
authors.initials: MY
authors.lastname: Tang
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; National University Health System (NUHS), Singapore.
authors.forename: Huifang
authors.initials: H
authors.lastname: Guo
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; National University Health System (NUHS), Singapore.
authors.forename: Thi Thuy Trang
authors.initials: TT
authors.lastname: Nguyen
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; National University Health System (NUHS), Singapore.
authors.forename: Liy Sim
authors.initials: LS
authors.lastname: Low
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Jackson
authors.affiliation: Department of Biological Sciences, Faculty of Science and Engineering, Chuo University, Japan.
authors.forename: Takatomi
authors.initials: T
authors.lastname: Yamada
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; National University Health System (NUHS), Singapore; Synthetic Biology Research Consortium, National University of Singapore, Singapore; NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore. Electronic address: bchces@nus.edu.sg.
authors.forename: Ee Sin
authors.initials: ES
authors.lastname: Chen
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D004249:DNA Damage; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology*; D025141:Drug Resistance, Fungal / Q000235:genetics; D004843:Epistasis, Genetic; D015966:Gene Expression Regulation, Fungal; D024002:HMGB Proteins / Q000235:genetics* / Q000378:metabolism; D059767:Recombinational DNA Repair; D012568:Schizosaccharomyces / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D024002:HMGB Proteins; D029702:Schizosaccharomyces pombe Proteins; D004317:Doxorubicin; D004265:DNA Helicases; C099034:Rhp54 protein, S pombe
keywords: Doxorubicin; Drug resistance; Fission yeast; Hap2; High mobility group; Nht1; Rhp54; S. pombe