Hedgehog signaling enables repair of ribosomal DNA double-strand breaks
Abstract
Ribosomal DNA (rDNA) consists of highly repeated sequences that are prone to incurring damage. Delays or failure of rDNA double-strand break (DSB) repair are deleterious, and can lead to rDNA transcriptional arrest, chromosomal translocations, genomic losses, and cell death. Here, we show that the zinc-finger transcription factor GLI1, a terminal effector of the Hedgehog (Hh) pathway, is required for the repair of rDNA DSBs. We found that GLI1 is activated in triple-negative breast cancer cells in response to ionizing radiation (IR) and localizes to rDNA sequences in response to both global DSBs generated by IR and site-specific DSBs in rDNA. Inhibiting GLI1 interferes with rDNA DSB repair and impacts RNA polymerase I activity and cell viability. Our findings tie Hh signaling to rDNA repair and this heretofore unknown function may be critically important in proliferating cancer cells.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Sep 07, 2020
- Source ID
- 10.1093/nar/gkaa733
Entities
People
- Brandon J. Metge
- Dongquan Chen
- Lalita A. Shevde
- Rajeev S Samant
- Shannon E Weeks
- Tshering D Lama-Sherpa
- Victor Lin
Organizations
- Birmingham VA Medical Center
- National Cancer Institute
- National Institutes of Health
- The Breast Cancer Research Foundation
- United States Department of Defense
- United States Department of Veterans Affairs
- University of Alabama at Birmingham