Novel Insights in DNA Damage Response at the Crossroads of Gene Expression: Hints from the 6th EU-US DNA Repair Meeting

Dear Colleagues, 

DNA is under constant attack from various exogenous and endogenous sources. Recent progress in whole genome sequencing has allowed many labs to identify an increasing array of cancer mutational signatures that serve as a high-resolution readout of the mutagenic processing of all of these sources of DNA damage that has accumulated over the lifetime of a patient. Moreover, specific signatures of DNA repair pathway alterations have emerged from these analyses thus revealing possible new targets for anticancer therapies. Interpreting these mutational signatures cannot be accomplished without a better understanding of the mechanisms involved in the formation or repair of such genome alterations. Various perturbations, originating from endogenous or exogenous sources, can interfere with the replication process, thus threatening genome integrity. Replication and the DNA damage response must be co-coordinated to ensure accurate DNA synthesis even under conditions of replication stress. Research is continuously identifying new factors involved in repair mechanisms/checkpoint machineries, which affect cell cycle progression until the damage is repaired.

The role of normal transcription and RNA processing in maintaining genome integrity is also becoming increasingly appreciated. We are only beginning to understand the nature and extent of the non-coding genome in human disease. New classes of RNAs and new regulatory mechanisms are emerging, expanding the known regulatory potential of small and long non-coding RNAs to encompass chromatin regulation. We are starting to learn that there are several variations of the DNA damage response (DDR) or the more global genomic stress response (GSR) in which pathways are activated by diverse cellular events and/or generates distinct signaling outcomes. In addition to cancer, defects in DNA repair and DDR pathways have been implicated in a wide array of diseases including neurodegeneration and age-related disorders. Recently, the DDR signaling cascade has been shown to function also in a paracrine manner triggering pro-inflammatory responses thus further extending its role in human health to metabolic diseases. Thus, there is reason to believe that the targeting of dysregulated repair/DDR processes may prove to be highly effective novel therapeutic approaches in the context of personalized medicine. A current challenge in our field is how to provide a holistic view of human health and disease considering that there are tens of thousands of chemicals in our environment. Exposures from our diet, our lifestyles, and our behaviors plus how our bodies respond to these challenges are currently assessed by evaluating the so-called exposome. This approach shows promise in deciphering disease mechanisms.

A major goal of this Special Issue is to describe the new frontiers in the molecular and cellular processes that affect genomic in human disease, in particular cancer, and the pathological changes associated with aging and genome instability in cancer. In particular, the emerging observations regarding the crosstalk between DNA Damage Response and Gene expression will be highlighted.

Papers will cover the following Topics:

• 1 - Replication Stress
• 2 - DNA editing: Mechanisms underlying mutational signatures in human cancers
• 3 - Regulatory mechanisms of RNA functions in genome stability
• 4 - Non-canonical action and novel regulators of DNA repair
• 5 - DNA damage, epigenetics and DNA repair
• 6 - Stability of the genome in aging and non-neoplastic disease
• 7 - Advanced technologies for analysis of DNA repair and the DNA damage response
• 8 - Poly(ADP-ribosyl)ation in the DNA damage response: Pre-clinical and translational aspects
• 9 - Defects in the DNA damage response as targets for personalized therapeutic approaches
• 10 - DNA repair and response to complex environmental genotoxins

Prof. Dr. Robert W. Sobol
Guest Editors

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