Cancer cells develop strong genetic dependencies, enabling survival under oncogenic stress. MYC is a key oncogene activated across most cancers, and identifying associated synthetic lethality or sickness can provide important clues about its activity and potential therapeutic strategies. On the basis of previously conducted genome-wide screenings in MCF10A cells expressing MYC fused to an estrogen receptor fragment, we identified UVSSA, a gene involved in transcription-coupled repair, whose knockdown or knockout decreased cell viability when combined with MYC expression. Synthetic sick interactions between MYC expression and UVSSA down-regulation correlated with ATM/CHK2 activation, suggesting increased genome instability. We show that the synthetic sick interaction is diminished by attenuating RNA polymerase II (RNAPII) activity; yet, it is independent of UV-induced damage repair, suggesting that UVSSA has a critical function in regulating RNAPII in the absence of exogenous DNA damage. Supporting this hypothesis, RNAPII ChIP-seq revealed that MYC-dependent increases in RNAPII promoter occupancy are reduced or abrogated by UVSSA knockdown, suggesting that UVSSA influences RNAPII dynamics during MYC-dependent transcription. Taken together, our data show that the UVSSA complex has a significant function in supporting MYC-dependent RNAPII dynamics and maintaining cell survival during MYC addiction. While the role of UVSSA in regulating RNAPII has been documented thus far only in the context of UV-induced DNA damage repair, we propose that its activity is also required to cope with transcriptional changes induced by oncogene activation.
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1 February 2021
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January 06 2021
The UVSSA complex alleviates MYC-driven transcription stress
Mai Sato
,
Mai Sato
1
Institute for Cancer Genetics, Columbia University Medical Center, New York, NY
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Andrew Walter Liebau
,
Andrew Walter Liebau
1
Institute for Cancer Genetics, Columbia University Medical Center, New York, NY
2
Department of Biology, Columbia University, New York, NY
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Zhaoqi Liu
,
Zhaoqi Liu
3
CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, China National Center for Bioinformation, Beijing, China
4
Program for Mathematical Genomics, Departments of Systems Biology and Biomedical Informatics, Columbia University, New York, NY
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Lizhi Liu
,
Lizhi Liu
2
Department of Biology, Columbia University, New York, NY
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Raul Rabadan
,
Raul Rabadan
4
Program for Mathematical Genomics, Departments of Systems Biology and Biomedical Informatics, Columbia University, New York, NY
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Jean Gautier
1
Institute for Cancer Genetics, Columbia University Medical Center, New York, NY
Correspondence to Jean Gautier: jg130@cumc.columbia.edu
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Mai Sato
1
Institute for Cancer Genetics, Columbia University Medical Center, New York, NY
Andrew Walter Liebau
1
Institute for Cancer Genetics, Columbia University Medical Center, New York, NY
2
Department of Biology, Columbia University, New York, NY
Zhaoqi Liu
3
CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, China National Center for Bioinformation, Beijing, China
4
Program for Mathematical Genomics, Departments of Systems Biology and Biomedical Informatics, Columbia University, New York, NY
Lizhi Liu
2
Department of Biology, Columbia University, New York, NY
Raul Rabadan
4
Program for Mathematical Genomics, Departments of Systems Biology and Biomedical Informatics, Columbia University, New York, NY
Jean Gautier
1
Institute for Cancer Genetics, Columbia University Medical Center, New York, NY
Correspondence to Jean Gautier: jg130@cumc.columbia.edu
Received:
November 05 2018
Revision Received:
October 05 2020
Accepted:
November 25 2020
Online Issn: 1540-8140
Print Issn: 0021-9525
Funding:
National Cancer Institute
(CA092245)
© 2020 Sato et al.
2020
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Cell Biol (2021) 220 (2): e201807163.
Article history
Received:
November 05 2018
Revision Received:
October 05 2020
Accepted:
November 25 2020
Citation
Mai Sato, Andrew Walter Liebau, Zhaoqi Liu, Lizhi Liu, Raul Rabadan, Jean Gautier; The UVSSA complex alleviates MYC-driven transcription stress. J Cell Biol 1 February 2021; 220 (2): e201807163. doi: https://doi.org/10.1083/jcb.201807163
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