Abstract
DNA double-strand breaks (DSBs) jeopardize genome integrity and can—when repaired unfaithfully—give rise to structural rearrangements associated with cancer. Exogenous agents such as ionizing radiation or chemotherapy can invoke DSBs, but a vast amount of breakage arises during vital endogenous DNA transactions, such as replication and transcription. Additionally, chromatin looping involved in 3D genome organization and gene regulation is increasingly recognized as a possible contributor to DSB events. In this review, we first discuss insights into the mechanisms of endogenous DSB formation, showcasing the trade-off between essential DNA transactions and the intrinsic challenges that these processes impose on genomic integrity. In the second part, we highlight emerging methods for genome-wide profiling of DSBs, and discuss future directions of research that will help advance our understanding of genome-wide DSB formation and repair.
Highlights
Out of the thousands of DNA insults that hit our cells every day [1], double-strand breaks (DSBs) are among the most deleterious lesions
DSBs play vital physiological roles—for example, in the context of planned genomic recombination, transcription, or replication fork rescue—any type of DSB represents a threat to the stability of the genome when faithful repair fails
The variety of methods to profile DSBs discussed in Part II, as well as their diverse applications, illustrates the complexity and diversity of the field of DSB identification, especially when one considers that genome-wide nucleotide-resolution methods only represent one of several angles to approach DSB biology
Summary
Out of the thousands of DNA insults that hit our cells every day [1], double-strand breaks (DSBs) are among the most deleterious lesions. While exogenous genotoxic insults contribute to this [7,8], in healthy individuals the majority of DSBs is thought to originate from within the nucleus, where DSBs form during fundamental processes such as DNA replication, meiosis, antibody diversification, gene transcription, and— indirectly—cellular metabolism [1,9,10,11,12,13]. Most DSB events are quickly sensed and—orchestrated by the cell’s DNA damage response (DDR) [1,7]—faithfully resolved by two partially redundant repair pathways: homologous recombination (HR) and classical non-homologous end-joining (C-NHEJ) [1,14]. Genes 2018, 9, 632 genome-wide DSB landscapes and we hypothesize how future efforts can help to answer some of the open questions that exist in the field
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