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Cell Cycle. 2017 Jan 17;16(2):189-199. doi: 10.1080/15384101.2016.1261765. Epub 2016 Dec 8.

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

Author information

1
a Genome-Scale Biology Program, University of Helsinki , Helsinki , Finland.
2
b Science for Life laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics , Karolinska Institutet , Stockholm , Sweden.
3
c Department of Medical Biochemistry and Biophysics , Karolinska Institutet , Stockholm , Sweden.

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.

KEYWORDS:

DNA replication; RNA interference; cancer; cell cycle; chromatin; functional genomics; nucleosome assembly; p53

PMID:
27929715
PMCID:
PMC5283814
DOI:
10.1080/15384101.2016.1261765
[Indexed for MEDLINE]
Free PMC Article

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