title: Genome-wide screen of cell-cycle regulators in normal and tumor cells identifies a differential response to nucleosome depletion.
abstract: To identify cell cycle regulators that enable cancer cells to replicate DNA and divide in an unrestricted manner, we performed a parallel genome-wide RNAi screen in normal and cancer cell lines. In addition to many shared regulators, we found that tumor and normal cells are differentially sensitive to loss of the histone genes transcriptional regulator CASP8AP2. In cancer cells, loss of CASP8AP2 leads to a failure to synthesize sufficient amount of histones in the S-phase of the cell cycle, resulting in slowing of individual replication forks. Despite this, DNA replication fails to arrest, and tumor cells progress in an elongated S-phase that lasts several days, finally resulting in death of most of the affected cells. In contrast, depletion of CASP8AP2 in normal cells triggers a response that arrests viable cells in S-phase. The arrest is dependent on p53, and preceded by accumulation of markers of DNA damage, indicating that nucleosome depletion is sensed in normal cells via a DNA-damage -like response that is defective in tumor cells.
authors.affiliation: a Genome-Scale Biology Program, University of Helsinki , Helsinki , Finland.
authors.forename: Maria
authors.initials: M
authors.lastname: Sokolova
authors.affiliation: a Genome-Scale Biology Program, University of Helsinki , Helsinki , Finland.
authors.forename: Mikko
authors.initials: M
authors.lastname: Turunen
authors.affiliation: b Science for Life laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics , Karolinska Institutet , Stockholm , Sweden.
authors.forename: Oliver
authors.initials: O
authors.lastname: Mortusewicz
authors.affiliation: a Genome-Scale Biology Program, University of Helsinki , Helsinki , Finland.
authors.forename: Teemu
authors.initials: T
authors.lastname: Kivioja
authors.affiliation: b Science for Life laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics , Karolinska Institutet , Stockholm , Sweden.
authors.forename: Patrick
authors.initials: P
authors.lastname: Herr
authors.affiliation: a Genome-Scale Biology Program, University of Helsinki , Helsinki , Finland.
authors.forename: Anna
authors.initials: A
authors.lastname: Vähärautio
authors.affiliation: a Genome-Scale Biology Program, University of Helsinki , Helsinki , Finland.
authors.forename: Mikael
authors.initials: M
authors.lastname: Björklund
authors.affiliation: c Department of Medical Biochemistry and Biophysics , Karolinska Institutet , Stockholm , Sweden.
authors.forename: Minna
authors.initials: M
authors.lastname: Taipale
authors.affiliation: b Science for Life laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics , Karolinska Institutet , Stockholm , Sweden.
authors.forename: Thomas
authors.initials: T
authors.lastname: Helleday
authors.affiliation: a Genome-Scale Biology Program, University of Helsinki , Helsinki , Finland.|c Department of Medical Biochemistry and Biophysics , Karolinska Institutet , Stockholm , Sweden.
authors.forename: Jussi
authors.initials: J
authors.lastname: Taipale
mesh_terms: D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004247:DNA / Q000096:biosynthesis; D004261:DNA Replication; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D016678:Genome; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009363:Neoplasm Proteins / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D009707:Nucleosomes / Q000378:metabolism*; D012516:Osteosarcoma / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D016196:S Phase; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; C468783:H2AX protein, human; D006657:Histones; D009363:Neoplasm Proteins; D009707:Nucleosomes; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D004247:DNA
keywords: DNA replication; RNA interference; cancer; cell cycle; chromatin; functional genomics; nucleosome assembly; p53