Prevention of Chromatin Destabilization by FACT Is Crucial for Malignant Transformation

Abstract

Histone chaperone FACT is commonly expressed and essential for the viability of transformed but not normal cells and its expression levels correlate with poor prognosis in cancer patients. FACT binds several components of nucleosomes and has been viewed as a factor destabilizing nucleosomes to facilitate RNA polymerase passage. To connect FACT’s role in transcription with the viability of tumor cells, we analyzed genome-wide FACT binding to chromatin in conjunction with transcription in mouse and human cells with different degrees of FACT dependence. While genomic distribution and density of FACT correlated with the intensity of transcription, FACT knockout or knockdown was unexpectedly accompanied by the elevation, rather than suppression, of transcription and with the destabilization of chromatin. These data suggest that the real function of FACT is to stabilize and reassemble nucleosomes disturbed by transcription. This function is apparently vital for tumor cells because malignant transformation is accompanied by chromatin destabilization.

Keywords: Cancer, Chromatin, SSRP1, SPT16, Malignant transformation, transcription, transcription elongation, nucleosome stability, p53, mutant ras, SSRP1 knockout