Mechanistic insights into KDM4A driven genomic instability

Alterations in global epigenetic signatures on chromatin are well established to contribute to tumor initiation and progression. Chromatin methylation status modulates several key cellular processes that maintain the integrity of the genome. KDM4A, a demethylase that belongs to the Fe-II dependent dioxygenase family that uses α-ketoglutarate and molecular oxygen as cofactors, is overexpressed in several cancers and is associated with an overall poor prognosis. KDM4A demethylates lysine 9 (H3K9me2/3) and lysine 36 (H3K36me3) methyl marks on histone H3. Given the complexity that exists with these marks on chromatin and their effects on transcription and proliferation, it naturally follows that demethylation serves an equally important role in these cellular processes. In this review, we highlight the role of KDM4A in transcriptional modulation, either dependent or independent of its enzymatic activity, arising from the amplification of this demethylase in cancer. KDM4A modulates re-replication of distinct genomic loci, activates cell cycle inducers, and represses proteins involved in checkpoint control giving rise to proliferative damage, mitotic disturbances and chromosomal breaks, ultimately resulting in genomic instability. In parallel, emerging evidence of non-nuclear substrates of epigenetic modulators emphasize the need to investigate the role of KDM4A in regulating non-nuclear substrates and evaluate their contribution to genomic instability in this context. The existence of promising KDM-specific inhibitors makes these demethylases an attractive target for therapeutic intervention in cancers.

Response of immunocompetent cells of bone marrow and spleen of mouse males of several strains to stress and to pyrazine containing chemosignals

The quantity of antibody producing cells and mitotic disturbances in dividing bone marrow cells of mice were studied after exposure of animals to a physical stressor or various pyrazinecontaining chemosignals. Several different strains of mice were used. We demonstrate that immune suppression and destabilization of the chromosome apparatus in dividing cells depend on: а) mouse genotype and b) side chains position in the pyrazine ring. Importance of this effects in the light of wide usage of pyrazine containing substances in perfume industry, food production and pharmacology is discussed.

Post-stress chemosignals affect cells from immunocompetent organs in laboratory mice of three inbred strains

Quantity of antibody producing cells and changes in bone marrow dividing cells of mouse males were studied after the exposure with chemosignals from intact or stressed donor mouse males. Inbred CBA, BALB/c and C57BL/6 strains were used. It is shown that excreted volatiles decrease quantity of antibody producing cells in spleen and at the same time raise the level of mitotic disturbances in bone marrow cells of recipient mice. Pheromone effect depends on genotype and physiological state of the recipients. For the first time we describe here the influence of mouse female pheromone 2,5-dimethylpyrazine on analyzed features. Biological meaning of the discovered effects is discussed.