Regional Gene Repression by DNA Double-Strand Breaks in G 1 Phase Cells

• Published in: Molecular and cellular biology 2019-12, Vol.39 (24)
• Main Authors: Purman, Caitlin E, Collins, Patrick L, Porter, Sofia I, Saini, Ankita, Gupta, Harshath, Sleckman, Barry P, Oltz, Eugene M
• Format: Article
• Language: English
• Subjects: Animals; Cell Cycle - genetics; Cell Line; DNA - genetics; DNA Breaks, Double-Stranded; DNA Damage - physiology; DNA End-Joining Repair - genetics; DNA Repair - genetics; DNA Repair - physiology; DNA-Binding Proteins - metabolism; G1 Phase - genetics; G1 Phase - physiology; Humans; Mice; Regulatory Elements, Transcriptional - genetics; Regulatory Elements, Transcriptional - physiology; Silencer Elements, Transcriptional - genetics; Silencer Elements, Transcriptional - physiology
• ISSN: 1098-5549; 1098-5549
• DOI: 10.1128/MCB.00181-19

DNA damage responses (DDR) to double-strand breaks (DSBs) alter cellular transcription programs at the genome-wide level. Through processes that are less well understood, DSBs also alter transcriptional responses locally, which may be important for efficient DSB repair. Here, we developed an approach to elucidate the -acting responses to DSBs in G phase cells. We found that DSBs within a gene body silence its expression, as well as the transcription of local undamaged genes at a distance defined by the spread of γ-H2AX from the DSB. Importantly, DSBs not only repress ongoing transcription but also block the inducible expression of regional genes. DSB-mediated transcriptional repression depends on DDR signaling but does not require the generation of inaccessible chromatin. Our findings demonstrate that in G phase cells, DDR signaling establishes a robust and extensive region of transcriptional repression spreading from DSB sites and introduce an approach to study the mechanistic impact of targeted DNA breaks in nearly any chromatin environment.