Cargando…

Ubiquitination-mediated degradation of TRDMT1 regulates homologous recombination and therapeutic response

The RNA methyltransferase TRDMT1 has recently emerged as a key regulator of homologous recombination (HR) in the transcribed regions of the genome, but how it is regulated and its relevance in cancer remain unknown. Here, we identified that TRDMT1 is poly-ubiquitinated at K251 by the E3 ligase TRIM2...

Descripción completa

Detalles Bibliográficos
Autores principales: Zhu, Xiaolan, Wang, Xiangyu, Yan, Wei, Yang, Haibo, Xiang, Yufei, Lv, Fengping, Shi, Yi, Li, Hong-yu, Lan, Li
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984809/
https://www.ncbi.nlm.nih.gov/pubmed/33778494
http://dx.doi.org/10.1093/narcan/zcab010
_version_ 1783668116568408064
author Zhu, Xiaolan
Wang, Xiangyu
Yan, Wei
Yang, Haibo
Xiang, Yufei
Lv, Fengping
Shi, Yi
Li, Hong-yu
Lan, Li
author_facet Zhu, Xiaolan
Wang, Xiangyu
Yan, Wei
Yang, Haibo
Xiang, Yufei
Lv, Fengping
Shi, Yi
Li, Hong-yu
Lan, Li
author_sort Zhu, Xiaolan
collection PubMed
description The RNA methyltransferase TRDMT1 has recently emerged as a key regulator of homologous recombination (HR) in the transcribed regions of the genome, but how it is regulated and its relevance in cancer remain unknown. Here, we identified that TRDMT1 is poly-ubiquitinated at K251 by the E3 ligase TRIM28, removing TRDMT1 from DNA damage sites and allowing completion of HR. Interestingly, K251 is adjacent to G155 in the 3D structure, and the G155V mutation leads to hyper ubiquitination of TRDMT1, reduced TRDMT1 levels and impaired HR. Accordingly, a TRDMT1 G155V mutation in an ovarian cancer super responder to platinum treatment. Cells expressing TRDMT1-G155V are sensitive to cisplatin in vitro and in vivo. In contrast, high expression of TRDMT1 in patients with ovarian cancer correlates with platinum resistance. A potent TRDMT1 inhibitor resensitizes TRDMT1-high tumor cells to cisplatin. These results suggest that TRDMT1 is a promising therapeutic target to sensitize ovarian tumors to platinum therapy.
format Online
Article
Text
id pubmed-7984809
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Oxford University Press
record_format MEDLINE/PubMed
spelling pubmed-79848092021-03-26 Ubiquitination-mediated degradation of TRDMT1 regulates homologous recombination and therapeutic response Zhu, Xiaolan Wang, Xiangyu Yan, Wei Yang, Haibo Xiang, Yufei Lv, Fengping Shi, Yi Li, Hong-yu Lan, Li NAR Cancer DNA Damage Sensing and Repair The RNA methyltransferase TRDMT1 has recently emerged as a key regulator of homologous recombination (HR) in the transcribed regions of the genome, but how it is regulated and its relevance in cancer remain unknown. Here, we identified that TRDMT1 is poly-ubiquitinated at K251 by the E3 ligase TRIM28, removing TRDMT1 from DNA damage sites and allowing completion of HR. Interestingly, K251 is adjacent to G155 in the 3D structure, and the G155V mutation leads to hyper ubiquitination of TRDMT1, reduced TRDMT1 levels and impaired HR. Accordingly, a TRDMT1 G155V mutation in an ovarian cancer super responder to platinum treatment. Cells expressing TRDMT1-G155V are sensitive to cisplatin in vitro and in vivo. In contrast, high expression of TRDMT1 in patients with ovarian cancer correlates with platinum resistance. A potent TRDMT1 inhibitor resensitizes TRDMT1-high tumor cells to cisplatin. These results suggest that TRDMT1 is a promising therapeutic target to sensitize ovarian tumors to platinum therapy. Oxford University Press 2021-03-22 /pmc/articles/PMC7984809/ /pubmed/33778494 http://dx.doi.org/10.1093/narcan/zcab010 Text en © The Author(s) 2021. Published by Oxford University Press on behalf of NAR Cancer. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle DNA Damage Sensing and Repair
Zhu, Xiaolan
Wang, Xiangyu
Yan, Wei
Yang, Haibo
Xiang, Yufei
Lv, Fengping
Shi, Yi
Li, Hong-yu
Lan, Li
Ubiquitination-mediated degradation of TRDMT1 regulates homologous recombination and therapeutic response
title Ubiquitination-mediated degradation of TRDMT1 regulates homologous recombination and therapeutic response
title_full Ubiquitination-mediated degradation of TRDMT1 regulates homologous recombination and therapeutic response
title_fullStr Ubiquitination-mediated degradation of TRDMT1 regulates homologous recombination and therapeutic response
title_full_unstemmed Ubiquitination-mediated degradation of TRDMT1 regulates homologous recombination and therapeutic response
title_short Ubiquitination-mediated degradation of TRDMT1 regulates homologous recombination and therapeutic response
title_sort ubiquitination-mediated degradation of trdmt1 regulates homologous recombination and therapeutic response
topic DNA Damage Sensing and Repair
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984809/
https://www.ncbi.nlm.nih.gov/pubmed/33778494
http://dx.doi.org/10.1093/narcan/zcab010
work_keys_str_mv AT zhuxiaolan ubiquitinationmediateddegradationoftrdmt1regulateshomologousrecombinationandtherapeuticresponse
AT wangxiangyu ubiquitinationmediateddegradationoftrdmt1regulateshomologousrecombinationandtherapeuticresponse
AT yanwei ubiquitinationmediateddegradationoftrdmt1regulateshomologousrecombinationandtherapeuticresponse
AT yanghaibo ubiquitinationmediateddegradationoftrdmt1regulateshomologousrecombinationandtherapeuticresponse
AT xiangyufei ubiquitinationmediateddegradationoftrdmt1regulateshomologousrecombinationandtherapeuticresponse
AT lvfengping ubiquitinationmediateddegradationoftrdmt1regulateshomologousrecombinationandtherapeuticresponse
AT shiyi ubiquitinationmediateddegradationoftrdmt1regulateshomologousrecombinationandtherapeuticresponse
AT lihongyu ubiquitinationmediateddegradationoftrdmt1regulateshomologousrecombinationandtherapeuticresponse
AT lanli ubiquitinationmediateddegradationoftrdmt1regulateshomologousrecombinationandtherapeuticresponse