Regulatory Networks in Genome Stability Pathways

Genetic alterations are major drivers of disease and cancer. Although only a small portion of DNA mutations confer cancer cells with a selective growth or survival advantage, those that do, facilitate the emergence of genetically altered cells that can evade cell death, proliferation limits, and immune checkpoints, and potentially metastasize throughout the body. In normal cells, genetic alterations are largely prevented by proteins of the genome stability pathways, which ensure that DNA is accurately replicated, DNA damages are rapidly repaired, and telomeres are protected. In cancers, the rate at which genetic alterations occur is frequently exacerbated by heritable or acquired mutations within proteins related to genomic maintenance, resulting in a state commonly referred to as “genomic instability”.

Proper DNA damage responses are essential for the maintenance of genome stability. They are achieved by complex regulatory networks of protein-protein interactions, activation/inactivation of enzymes and multi-step signalling cascades. Post-translational modifications including phosphorylation, acetylation, methylation, ubiquitination, SUMOylation, NEDDylation, ISGylation and PARylation, play critical roles in regulating the genome stability pathways. These modifications can alter protein stability, create binding sites that mediate protein-protein interactions and induce steric alterations to modulate protein activity. In doing so, post-translational modifications can regulate diverse outcomes such as cell cycle arrest, altered replication dynamics, telomere lengthening and chromatin remodelling. The central importance of these events to normal cellular function is demonstrated by their frequent mutation/deregulation in many cancers.

In this Research Topic, we aim to highlight recent advances in understanding the essential roles regulatory networks play in ensuring genome stability. We welcome the submission of Original Research and Review articles on the following topics:
• Modulation (up or down-regulation) of regulatory enzymes in the genome stability pathways;
• Post-translational regulation of DNA replication and repair proteins;
• Post-translational signalling in telomere maintenance;
• Macromolecular complex formation in the DNA damage response;
• Chromatin modification at DNA replication and repair sites;
• The contribution of genome stability deregulation to tumorigeneses and cancer progression;
• Exploring systemic effects and/or applying genome-wide or large scale experimental or computational analysis methodologies.