HSATII RNA is induced via a noncanonical ATM-regulated DNA damage response pathway and promotes tumor cell proliferation and movement.

Abstract

Pericentromeric human satellite II (HSATII) repeats are normally silent but can be actively transcribed in tumor cells, where increased HSATII copy number is associated with a poor prognosis in colon cancer, and in human cytomegalovirus (HCMV)-infected fibroblasts, where the RNA facilitates viral replication. Here, we report that HCMV infection or treatment of ARPE-19 diploid epithelial cells with DNA-damaging agents, etoposide or zeocin, induces HSATII RNA expression, and a kinase-independent function of ATM is required for the induction. Additionally, various breast cancer cell lines growing in adherent, two-dimensional cell culture express HSATII RNA at different levels, and levels are markedly increased when cells are infected with HCMV or treated with zeocin. High levels of HSATII RNA expression correlate with enhanced migration of breast cancer cells, and knockdown of HSATII RNA reduces cell migration and the rate of cell proliferation. Our investigation links high expression of HSATII RNA to the DNA damage response, centered on a noncanonical function of ATM, and demonstrates a role for the satellite RNA in tumor cell proliferation and movement.

• Authors: Maciej T Nogalski, Thomas Shenk
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 117 Issue 50 Pg. 31891-31901 (12 15 2020) ISSN: 1091-6490 [Electronic] United States
• PMID: 33257565 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• DNA, Satellite
• RNA, Untranslated
• Bleomycin
• Zeocin
• Etoposide
• ATM protein, human
• Ataxia Telangiectasia Mutated Proteins

Topics

• Ataxia Telangiectasia Mutated Proteins (metabolism)
• Bleomycin (pharmacology, therapeutic use)
• Breast Neoplasms (drug therapy, genetics, pathology, virology)
• Cell Line, Tumor
• Cell Movement (genetics)
• Cell Proliferation (genetics)
• Cytomegalovirus Infections (genetics, pathology, virology)
• DNA Damage (drug effects)
• DNA Repair
• DNA, Satellite (genetics)
• Disease Progression
• Etoposide (pharmacology, therapeutic use)
• Female
• Gene Expression Regulation, Neoplastic
• Gene Knockdown Techniques
• Genetic Fitness (drug effects)
• Humans
• RNA, Untranslated (genetics, metabolism)
• RNA-Seq
• Repetitive Sequences, Nucleic Acid
• Transcriptional Activation (drug effects)