DNA double-strand breaks (DSBs) are major DNA lesions that are constantly formed 
during physiological processes such as DNA replication, transcription, and 
recombination, or as a result of exogenous agents such as ionizing radiation, 
radiomimetic drugs, and genome editing nucleases. Unrepaired DSBs threaten 
genomic stability by leading to the formation of potentially oncogenic 
rearrangements such as translocations. In past few years, several methods based 
on next-generation sequencing (NGS) have been developed to study the genome-wide 
distribution of DSBs or their conversion to translocation events. We developed 
Breaks Labeling, Enrichment on Streptavidin, and Sequencing (BLESS), which was 
the first method for direct labeling of DSBs in situ followed by their 
genome-wide mapping at nucleotide resolution (Crosetto et al., Nat Methods 
10:361-365, 2013). Recently, we have further expanded the quantitative nature, 
applicability, and scalability of BLESS by developing Breaks Labeling In Situ 
and Sequencing (BLISS) (Yan et al., Nat Commun 8:15058, 2017). Here, we first 
present an overview of existing methods for genome-wide localization of DSBs, 
and then focus on the BLESS and BLISS methods, discussing different assay design 
options depending on the sample type and application.