Abstract
Single-stranded DNA (ssDNA) arising as an intermediate of cellular processes on DNA is a potential vulnerability of the genome unless it is appropriately protected. Recent evidence suggests that R-loops, consisting of ssDNA and DNA-RNA hybrids, can form in the proximity of DNA double-strand breaks (DSBs) within transcriptionally active regions. However, how the vulnerability of ssDNA in R-loops is overcome during DSB repair remains unclear. Here, we identify RAP80 as a factor suppressing the vulnerability of ssDNA in R-loops, chromosome translocations, and deletions during DSB repair. Mechanistically, RAP80 prevents unscheduled nucleolytic processing of ssDNA in R-loops by CtIP. This mechanism promotes efficient DSB repair via transcription-associated end joining dependent on BRCA1, Polθ, and LIG1/3. Thus, RAP80 suppresses the vulnerability of R-loops during DSB repair, thereby precluding genomic abnormalities in a critical component of the genome caused by deleterious R-loop processing.
Highlights
DNA double-strand breaks (DSBs) are a source of genomic instability, such as deletions, insertions, and chromosome translocations, which eventually lead to various disorders, including genetic diseases and cancer
We identify RAP80 as a key factor suppressing the vulnerability of Single-stranded DNA (ssDNA) in R-loops during DSB repair, thereby preventing abnormalities in transcribed regions of the genome
RAP80 is a suppressor of genomic abnormalities within gene regions in cancer To identify the factors precluding genomic instability in gene regions, we exploited The Cancer Genome Atlas (TCGA) database to screen for genes whose low expression is associated with increased deletion risk within gene regions or gene fusion events (Yoshihara et al, 2015)
Summary
DNA double-strand breaks (DSBs) are a source of genomic instability, such as deletions, insertions, and chromosome translocations, which eventually lead to various disorders, including genetic diseases and cancer. Many roles of RNA in DSB repair at transcription active regions have been suggested; RNA serves as a repair template (Chakraborty et al, 2016; Keskin et al, 2014), forms a DNA-RNA hybrid to recruit repair factors (d’Adda di Fagagna, 2014), and triggers a special type of repair pathway, such as transcription-associated (TA) homologous recombination repair (HRR) (Aymard et al, 2014; Ohle et al, 2016; Yasuhara et al, 2018) These mechanisms contribute to maintenance of the actively transcribed regions and protect the most important regions of the genome from genotoxic stresses. TA-HRR in S/G2 cells does not function in G1 cells, raising the question of what pathway is responsible for the repair of this class of DSBs in G1 cells
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