Kanne, Julian, Hussong, Michelle, Isensee, Joerg, Munoz-Lopez, Alvaro, Wolffgramm, Jan, Hess, Felix, Grimm, Christina ORCID: 0000-0002-4676-8870, Bessonov, Sergey, Meder, Lydia, Wang, Jie, Reinhardt, H. Christian, Odenthal, Margarete, Hucho, Tim ORCID: 0000-0002-4147-9308, Buettner, Reinhard, Summerer, Daniel and Schweiger, Michal R. (2021). Pericentromeric Satellite III transcripts induce etoposide resistance. Cell Death Dis., 12 (6). LONDON: SPRINGERNATURE. ISSN 2041-4889

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Abstract

Non-coding RNA from pericentromeric satellite repeats are involved in stress-dependent splicing processes, maintenance of heterochromatin, and are required to protect genome stability. Here we show that the long non-coding satellite III RNA (SatIII) generates resistance against the topoisomerase IIa (TOP2A) inhibitor etoposide in lung cancer. Because heat shock conditions (HS) protect cells against the toxicity of etoposide, and SatIII is significantly induced under HS, we hypothesized that the protective effect could be traced back to SatIII. Using genome methylation profiles of patient-derived xenograft mouse models we show that the epigenetic modification of the SatIII DNA locus and the resulting SatIII expression predict chemotherapy resistance. In response to stress, SatIII recruits TOP2A to nuclear stress bodies, which protects TOP2A from a complex formation with etoposide and results in decreased DNA damage after treatment. We show that BRD4 inhibitors reduce the expression of SatIII, restoring etoposide sensitivity.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Kanne, JulianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hussong, MichelleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Isensee, JoergUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Munoz-Lopez, AlvaroUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wolffgramm, JanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hess, FelixUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grimm, ChristinaUNSPECIFIEDorcid.org/0000-0002-4676-8870UNSPECIFIED
Bessonov, SergeyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meder, LydiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wang, JieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reinhardt, H. ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Odenthal, MargareteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hucho, TimUNSPECIFIEDorcid.org/0000-0002-4147-9308UNSPECIFIED
Buettner, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Summerer, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schweiger, Michal R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-587038
DOI: 10.1038/s41419-021-03810-9
Journal or Publication Title: Cell Death Dis.
Volume: 12
Number: 6
Date: 2021
Publisher: SPRINGERNATURE
Place of Publication: LONDON
ISSN: 2041-4889
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
TOPOISOMERASE-II; DIFFERENTIAL EXPRESSION; DNA TOPOISOMERASES; READ ALIGNMENT; HETEROCHROMATIN; VISUALIZATION; HISTONE; CANCER; ACTIVATION; CLEAVAGEMultiple languages
Cell BiologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/58703

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