Maintenance of chromatin

stability in mammalian cells

          Each round of replication and transcription requires disassembly and re-assembly of chromatin. With increasing number of cycles and moreover with their acceleration and loss of checkpoint control mechanisms, occurring in tumor, one would expect gradual degradation and eventual loss of chromatin in cells of advanced cancers. However, this does not occur. Moreover, based on transcriptional profiles, tissue of origin of almost any tumor can be easily recognized, even when tumor cells lose any “geographical” connection with original tissue, such as upon metastasizing or being propagated as cell culture in vitro. Since transcriptional profile is defined by chromatin organization, this means that in general chromatin structure is preserved in tumor cells.  So why HeLa cell with 82 chromosomes living for more than half a century in a dish still continue to be cervical epithelial cell?

        Therefore, there should be a system in cells to prevent nucleosome loss during different cellular processes, either via constant rebuilding of nucleosome or via prevention of their loss. This is so called system of positive reinforcement. However, withstanding entropy does not come without costs. Thus, there may be also a system(s) of negative reinforcement, which detect chromatin disassembly and eliminate cells with destabilized chromatin, similar to the one which eliminates cells with destabilized genome.

Regulation of chromatin stability in mammalian cells 



Transcription and replication constantly disturbs contact of histones with DNA and therefore may "degrade" chromatin. However, chromatin is not "degraded" even in tumor cells, in which both processes are significantly accelerated. This suggests that there should be a system to monitor and maintain chromatin composition to avoid loss of epigenetic marks and differentiation.   We propose that this may be achieved via two ways: positive reinforcement or constant repair of the chromatin and negative reinforcement or elimination of cells with damaged chromatin. Although neither of these systems is clearly described, our data suggest existence of both of them.

Our recent findings:


We showed that FACT is one of the major sensors of chromatin destabilization. It detects nucleosome disassembly and binds destabilized nucleosomes via SPT16 subunits, and DNA undergoing super-helical transitions due to nucleosome loss via SSRP1 subunits. There are at least two DNA binding domains on c-terminus of SSRP1, HMG box which can bind bended or cruciform DNA and CID which binds left-handed Z-DNA.

How FACT detects chromatin destabilization: model of the mechanism of c-trapping. The upper panel shows the scheme of the nucleosome with a standard color code for core histones (H2A-yellow, H2B – red, H3 – blue, H4 – green) and the domain structure of FACT subunits (NTD – N-terminal domain, DD – dimerization domain, MD – middle domain). The lower panels show two phases of c-trapping: i) n(nucleosome)-trapping that occurs via the SPT16 subunit binding to the hexasome of the partially uncoiled nucleosome when one molecule of CBL0137 is bound per ∼10–100 bp of DNA; ii) z(Z-DNA)-trapping that occurs via SSRP1 subunit binding to DNA when the nucleosome is disassembled upon binding of one or more molecules of CBL0137 to every 10 bp of DNA.

Chromatin destabilization in cells is accompanied by de-silencing of heterochromatin, accumulation of double stranded RNA due to transcription of repetitive heterochromatic elements and induction of type I interferon response. Since interferon may induce apoptosis - this mechanism may be responsible for elimination of cells with destabilized chromatin.

Proposed consequences of chromatin destabilization in mammalian cells:

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