title: The Impact of dUTPase on Ribonucleotide Reductase-Induced Genome Instability in Cancer Cells.
abstract: The appropriate supply of dNTPs is critical for cell growth and genome integrity. Here, we investigated the interrelationship between dUTP pyrophosphatase (dUTPase) and ribonucleotide reductase (RNR) in the regulation of genome stability. Our results demonstrate that reducing the expression of dUTPase increases genome stress in cancer. Analysis of clinical samples reveals a significant correlation between the combination of low dUTPase and high R2, a subunit of RNR, and a poor prognosis in colorectal and breast cancer patients. Furthermore, overexpression of R2 in non-tumorigenic cells progressively increases genome stress, promoting transformation. These cells display alterations in replication fork progression, elevated genomic uracil, and breaks at AT-rich common fragile sites. Consistently, overexpression of dUTPase abolishes R2-induced genome instability. Thus, the expression level of dUTPase determines the role of high R2 in driving genome instability in cancer cells.
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 112, Taiwan.
authors.forename: Chih-Wei
authors.initials: CW
authors.lastname: Chen
authors.affiliation: Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
authors.forename: Ning
authors.initials: N
authors.lastname: Tsao
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 112, Taiwan.
authors.forename: Lin-Yi
authors.initials: LY
authors.lastname: Huang
authors.affiliation: Department of Molecular Pharmacology, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA 91010, USA; Taipei Medical University, Taipei 110, Taiwan.
authors.forename: Yun
authors.initials: Y
authors.lastname: Yen
authors.affiliation: Taipei Medical University, Taipei 110, Taiwan; California Cancer Institute, Sino-American Cancer Foundation, Temple City, CA 91780, USA.
authors.forename: Xiyong
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Cancer Biology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1016, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Lehman
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
authors.forename: Yuh-Hwa
authors.initials: YH
authors.lastname: Wang
authors.affiliation: Institute of Chemistry, Academia Sinica, Nankang, Taipei 115, Taiwan.
authors.forename: Mei-Chun
authors.initials: MC
authors.lastname: Tseng
authors.affiliation: Department of Chemistry, National Taiwan University, Taipei 100, Taiwan; Institute of Chemistry, Academia Sinica, Nankang, Taipei 115, Taiwan.
authors.forename: Yu-Ju
authors.initials: YJ
authors.lastname: Chen
authors.affiliation: Institute of Chemistry, Academia Sinica, Nankang, Taipei 115, Taiwan.
authors.forename: Yi-Chi
authors.initials: YC
authors.lastname: Ho
authors.affiliation: VYM Genome Research Center, National Yang-Ming University, Taipei 112, Taiwan.
authors.forename: Chian-Feng
authors.initials: CF
authors.lastname: Chen
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 112, Taiwan. Electronic address: zfchang@ym.edu.tw.
authors.forename: Zee-Fen
authors.initials: ZF
authors.lastname: Chang
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D043283:Chromosome Fragile Sites / Q000235:genetics; D005260:Female; D042822:Genomic Instability / Q000235:genetics*; D019073:HT29 Cells; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000235:genetics*; D011379:Prognosis; D011755:Pyrophosphatases / Q000235:genetics*; D012264:Ribonucleotide Reductases / Q000235:genetics*
chemical_list: D012264:Ribonucleotide Reductases; D011755:Pyrophosphatases; C020020:dUTP pyrophosphatase