Genome-wide screen of cell-cycle regulators in normal and tumor cells identifies a differential response to nucleosome depletion

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...

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Bibliographic Details
Published in:Cell cycle (Georgetown, Tex.) Tex.), 2017-01, Vol.16 (2), p.189-199
Main Authors: Sokolova, Maria, Turunen, Mikko, Mortusewicz, Oliver, Kivioja, Teemu, Herr, Patrick, Vähärautio, Anna, Björklund, Mikael, Taipale, Minna, Helleday, Thomas, Taipale, Jussi
Format: Article
Language:English
Subjects:
Cell Cycle
Cell Cycle Proteins - genetics
Cell Cycle Proteins - metabolism
Cell Line, Tumor
DNA - biosynthesis
DNA Replication
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Genome
Histones - genetics
Histones - metabolism
Humans
Medicin och hälsovetenskap
Neoplasm Proteins - metabolism
Neoplasms - metabolism
Neoplasms - pathology
Nucleosomes - metabolism
Osteosarcoma - genetics
Osteosarcoma - pathology
Phosphorylation
RNA Interference
RNA, Small Interfering - metabolism
S Phase
Transcription, Genetic
Tumor Suppressor Protein p53 - metabolism
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Summary: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.
ISSN:1538-4101
1551-4005
1551-4005
DOI:10.1080/15384101.2016.1261765