Hedgehog signaling enables repair of ribosomal DNA double-strand breaks

Tshering D Lama-Sherpa; Victor T G Lin; Brandon J Metge; Shannon E Weeks; Dongquan Chen; Rajeev S Samant; Lalita A Shevde

doi:10.1093/nar/gkaa733

Hedgehog signaling enables repair of ribosomal DNA double-strand breaks

Nucleic Acids Res. 2020 Oct 9;48(18):10342-10352. doi: 10.1093/nar/gkaa733.

Authors

Tshering D Lama-Sherpa¹, Victor T G Lin^{2

3}, Brandon J Metge¹, Shannon E Weeks¹, Dongquan Chen^{3

4}, Rajeev S Samant^{1

3

5}, Lalita A Shevde^{1

3}

Affiliations

¹ Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL, USA.
² Division of Hematology and Oncology, Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA.
³ O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, AL, USA.
⁴ Division of Preventative Medicine, Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA.
⁵ Birmingham VA Medical Center, Birmingham, AL, USA.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Cell Cycle Proteins / genetics
Cell Nucleolus / genetics
Cell Nucleolus / radiation effects
Cell Proliferation / radiation effects
Cell Survival / radiation effects
DNA Breaks, Double-Stranded / radiation effects
DNA Damage / radiation effects
DNA Repair / radiation effects
DNA, Ribosomal / genetics*
DNA, Ribosomal / radiation effects
Gene Expression Regulation / genetics
Gene Expression Regulation / radiation effects
Hedgehog Proteins / genetics*
Humans
RNA Polymerase I / genetics*
RNA Polymerase I / radiation effects
Radiation, Ionizing
Ribosomes / genetics
Ribosomes / radiation effects
Signal Transduction / radiation effects
Transcription, Genetic / genetics
Triple Negative Breast Neoplasms / genetics
Triple Negative Breast Neoplasms / pathology
Triple Negative Breast Neoplasms / radiotherapy*
Zinc Finger Protein GLI1 / genetics*

Substances

Cell Cycle Proteins
DNA, Ribosomal
GLI1 protein, human
Hedgehog Proteins
Zinc Finger Protein GLI1
RNA Polymerase I

Abstract

Publication types

MeSH terms

Substances

Grants and funding