To Join or Not to Join: Decision Points Along the Pathway to Double-Strand Break Repair vs. Chromosome End Protection.

Stephanie M. Ackerson,Carlan Romney,P. Logan Schuck,Jason A. Stewart

doi:10.3389/fcell.2021.708763

Stephanie M. Ackerson, Carlan Romney + Show 2 more

Open Access

https://doi.org/10.3389/fcell.2021.708763

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Abstract

The regulation of DNA double-strand breaks (DSBs) and telomeres are diametrically opposed in the cell. DSBs are considered one of the most deleterious forms of DNA damage and must be quickly recognized and repaired. Telomeres, on the other hand, are specialized, stable DNA ends that must be protected from recognition as DSBs to inhibit unwanted chromosome fusions. Decisions to join DNA ends, or not, are therefore critical to genome stability. Yet, the processing of telomeres and DSBs share many commonalities. Accordingly, key decision points are used to shift DNA ends toward DSB repair vs. end protection. Additionally, DSBs can be repaired by two major pathways, namely homologous recombination (HR) and non-homologous end joining (NHEJ). The choice of which repair pathway is employed is also dictated by a series of decision points that shift the break toward HR or NHEJ. In this review, we will focus on these decision points and the mechanisms that dictate end protection vs. DSB repair and DSB repair choice.

Highlights

DNA double strand breaks (DSBs) originate from exposure to both external DNA damaging agents, such as genotoxic chemicals and ionizing radiation (IR), and endogenous sources, such replication fork collapse, reactive oxygen species and chromosome fusions (Symington and Gautier, 2011; Ceccaldi et al, 2016)
As described above, preventing stable binding and localization of homologous recombination (HR) factors is the major mechanism used to prevent unwanted “repair” at telomeres, but what happens when replication protein A (RPA) remains stably bound to G-overhangs? Loss of protection of telomeres 1 (POT1) or CST results in telomeric RPA foci but surprisingly only a minor increase in chromosome fusions, in comparison to TRF2 loss (Denchi and de Lange, 2007; Feng et al, 2017)
While our understanding of double-strand breaks (DSBs) recognition and repair has progressed by leaps and bounds in recent years, important questions remain unanswered

Summary

Introduction

DNA double strand breaks (DSBs) originate from exposure to both external DNA damaging agents, such as genotoxic chemicals and ionizing radiation (IR), and endogenous sources, such replication fork collapse, reactive oxygen species and chromosome fusions (Symington and Gautier, 2011; Ceccaldi et al, 2016). MRN can function at both unblocked and blocked DNA ends to promote resection of the DSB (Figure 4). When both Ku and MRN are bound, stimulation of the MRN nuclease activity promotes resection and the removal of Ku. MRN can function at ends blocked by a protein adduct, damaged bases or DNA secondary structures.

Results

Conclusion