Transcription-replication conflicts: How they occur and how they are resolved

The frequent occurrence of transcription and DNA replication in cells results in many encounters, and thus conflicts, between the transcription and replication machineries. These conflicts constitute a major intrinsic source of genome instability, which is a hallmark of cancer cells. How the replication machinery progresses along a DNA molecule occupied by an RNA polymerase is an old question. Here we review recent data on the biological relevance of transcription-replication conflicts, and the factors and mechanisms that are involved in either preventing or resolving them, mainly in eukaryotes. On the basis of these data, we provide our current view of how transcription can generate obstacles to replication, including torsional stress and non-B DNA structures, and of the different cellular processes that have evolved to solve them

Role of Cortisol and Dehydroepiandrosterone on RACK1/PKC Signalling and Consequences in Immunosenescence

Over the past 15 years, it was demonstrated that defective protein kinase C (PKC) signal transduction machinery correlates to the decline of immune functions associated with aging. Experimental evidence suggest that altered PKC signalling results in impaired response to lipopolisaccaride (LPS) stimulation and cytokine release. Such defective signalling is due to reduced expression of receptor for activated C kinase 1 (RACK1) and to age-related alteration of the hormonal balance between cortisol and dehydroepiandrosterone (DHEA): cortisol levels remain substantially unchanged while DHEA levels decline with aging. These aspects are particularly relevant for the functional PKC signalling system because DHEA administration in vivo and in vitro in aged animals and in human cells can reestablish the levels of RACK1 and thus the function of the PKC signalling cascade. There is also evidence that cortisol and DHEA have opposite effect on the transcriptional regulation of the gene encoding for RACK1 and known as GNB2L1. At transcriptional level, cortisol has a peculiar function of a negative regulator of the RACK1 promoter, while the effect of DHEA seems to derive from a complex influence on the functions and post-transcriptional regulation of the glucocorticoid receptor (GR). Here we discuss the role of PKC/RACK1 signalling in the context of immune cells and immunosenescence also focusing on the role of cortisol and DHEA in the regulation of RACK1 expression