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

TitleHSATII RNA is induced via a noncanonical ATM-regulated DNA damage response pathway and promotes tumor cell proliferation and movement.
Publication TypeJournal Article
Year of Publication2020
AuthorsNogalski, MT, Shenk, T
JournalProc Natl Acad Sci U S A
Volume117
Issue50
Pagination31891-31901
Date Published2020 12 15
ISSN1091-6490
KeywordsAtaxia Telangiectasia Mutated Proteins, Bleomycin, Breast Neoplasms, Cell Line, Tumor, Cell Movement, Cell Proliferation, Cytomegalovirus Infections, Disease Progression, DNA Damage, DNA Repair, DNA, Satellite, Etoposide, Female, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Genetic Fitness, Humans, Repetitive Sequences, Nucleic Acid, RNA, Untranslated, RNA-Seq, Transcriptional Activation
Abstract

<p>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.</p>

DOI10.1073/pnas.2017734117
Alternate JournalProc Natl Acad Sci U S A
PubMed ID33257565
PubMed Central IDPMC7749351
Grant ListR01 AI112951 / AI / NIAID NIH HHS / United States
R21 AI142520 / AI / NIAID NIH HHS / United States
R56 AI112951 / AI / NIAID NIH HHS / United States