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DNA Repair in Space and Time: Safeguarding the Genome with the Cohesin Complex

Jamie Phipps¹, Karine Dubrana¹

¹UMR Stabilité Génétique Cellules Souches et Radiations, INSERM, iRCM/IBFJ CEA, Université de Paris and Université Paris-Saclay, F-92265 Fontenay-aux-Roses, France.

|February 25, 2022

Abstract:

DNA double-strand breaks (DSBs) are a deleterious form of DNA damage, which must be robustly addressed to ensure genome stability. Defective repair can result in chromosome loss, point mutations, loss of heterozygosity or chromosomal rearrangements, which could lead to oncogenesis or cell death. We explore the requirements for the successful repair of DNA DSBs by non-homologous end joining and homology-directed repair (HDR) mechanisms in relation to genome folding and dynamics. On the occurrence of a DSB, local and global chromatin composition and dynamics, as well as 3D genome organization and break localization within the nuclear space, influence how repair proceeds. The cohesin complex is increasingly implicated as a key regulator of the genome, influencing chromatin composition and dynamics, and crucially genome organization through folding chromosomes by an active loop extrusion mechanism, and maintaining sister chromatid cohesion. Here, we consider how this complex is now emerging as a key player in the DNA damage response, influencing repair pathway choice and efficiency.

Insights

DNA double-strand breaks (DSBs) require robust repair for genome stability. The cohesin complex plays a crucial role in DNA repair pathway choice and efficiency, influencing chromatin dynamics and genome organization.

Area of Science:

Molecular Biology
Genetics
Cell Biology

Background:

DNA double-strand breaks (DSBs) are critical DNA damage events.
Defective DSB repair can lead to genomic instability, mutations, and cancer.
Genome folding, dynamics, and 3D organization influence DSB repair outcomes.

Purpose of the Study:

To explore the requirements for successful DSB repair via non-homologous end joining and homology-directed repair (HDR).
To investigate the role of genome folding, dynamics, and 3D organization in DSB repair.
To elucidate the emerging role of the cohesin complex in DNA damage response.

Main Methods:

Review of existing literature on DSB repair mechanisms.
Analysis of the influence of chromatin composition, dynamics, and 3D genome organization on repair.
Focus on the function of the cohesin complex in DNA repair.

Main Results:

DSB repair is influenced by local/global chromatin status and 3D genome organization.
The cohesin complex regulates chromatin dynamics and genome folding via loop extrusion.
Cohesin is emerging as a key regulator of DNA damage response, impacting repair pathway choice and efficiency.

Conclusions:

Successful DSB repair is intricately linked to genome architecture and dynamics.
The cohesin complex is a critical factor modulating DNA repair processes.
Understanding cohesin's role is vital for comprehending genome stability and disease prevention.

Read full analysis

Keywords:

DNA repair NHEJ chromatin chromatin dynamics cohesin homologous recombination nuclear organization

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