Research Topic

Protecting the Code: DNA Double-Strand Break Repair Pathway Choice

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About this Research Topic

Endogenous and exogenous DNA damage can lead to a wide variety of DNA lesions. DNA double-strand breaks (DSB) represent one of the most toxic types of damage. Such breaks threaten the stability of our DNA since they can fracture the architecture of our chromosomes. Improperly repaired breaks can lead to ...

Endogenous and exogenous DNA damage can lead to a wide variety of DNA lesions. DNA double-strand breaks (DSB) represent one of the most toxic types of damage. Such breaks threaten the stability of our DNA since they can fracture the architecture of our chromosomes. Improperly repaired breaks can lead to diseases such as immune disorders and cancer. On the other hand, the targeted generation of DSBs can be exploited for CRISPR-mediated genome editing and gene therapy. DSB repair is, therefore, one of the most critical tasks a cell must pursue to maintain genome integrity, with important clinical implications.

With an ever-growing number of studies, decades of research have revealed the complexity of the cellular response and repair molecules involved in detecting, signalling, and repairing DSBs. We now know that there are at least four separate pathways for DSB repair. Intriguingly, the different pathways show different fidelity levels, where homologous recombination is the most faithful mechanism for repair. At the same time, classical non-homologous end-joining, alternative end-joining, and single-strand annealing are considered more error-prone types of repair. Therefore, the repair of DSBs must be an orchestrated sequence of events that requires crosstalk between factors of the different pathways and crosstalk with other cellular processes such as transcription and replication. Major determinants in the choice of repair pathway seem to lie in a combination of the cell cycle stage, lesion complexity, chromatin context, and other, likely still unidentified factors.

In this Research Topic, we aim to provide an overview of recent discoveries and methodologies to understand how cells commit to each DSB repair pathway. Our primary interest will be focusing on the critical factors involved and the interplay between the different repair mechanisms. We will also look for research directed at utilizing the cellular DSB response for targeted genome editing. Furthermore, we will highlight research aiming to understand better the role of DSB repair in human health and diseases, especially on how altering repair processes could lead to diseases such as cancer and immune disorder. This Research Topic is interested in Original Research, Methods, and Review Articles papers including, but not limited to, the following themes:
• Causes of DSB formation (e.g., spontaneous chromosome breakage, transcription-replication conflicts and dysfunctional replication fork processing, telomere deprotection);
• DSB repair pathway choice in (somatic) mammalian cells - Cellular factors involved in DSB repair pathway choice;
• Current methods and technologies to explore DSB repair pathway choice;
• Utilization and manipulation of DSB repair to improve targeted genome editing;
• Synthetic lethality between different DSB repair pathways and its clinical implications;
• Crosstalk between transcription, mRNA processing, replication, cell cycle control, and DNA repair;
• Disease risk or predisposition due to defects in DNA double-strand break repair.


Keywords: DNA Double strand break repair, DSB pathway choice, end-resection, DSB reporters, DSB factors


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