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Prostate cancer-associated SPOP mutations lead to genomic instability through disruption of the SPOP–HIPK2 axis
Speckle-type Poz protein (SPOP), an E3 ubiquitin ligase adaptor, is the most frequently mutated gene in prostate cancer. The SPOP-mutated subtype of prostate cancer shows high genomic instability, but the underlying mechanisms causing this phenotype are still largely unknown. Here, we report that up...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266658/ https://www.ncbi.nlm.nih.gov/pubmed/34133717 http://dx.doi.org/10.1093/nar/gkab489 |
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author | Jin, Xiaofeng Qing, Shi Li, Qian Zhuang, Hui Shen, Liliang Li, Jinhui Qi, Honggang Lin, Ting Lin, Zihan Wang, Jian Cao, Xinyi Yang, Jianye Ma, Qi Cong, Linghua Xi, Yang Fang, Shuai Meng, Xiaodan Gong, Zhaohui Ye, Meng Wang, Shuyun Wang, Chenji Gao, Kun |
author_facet | Jin, Xiaofeng Qing, Shi Li, Qian Zhuang, Hui Shen, Liliang Li, Jinhui Qi, Honggang Lin, Ting Lin, Zihan Wang, Jian Cao, Xinyi Yang, Jianye Ma, Qi Cong, Linghua Xi, Yang Fang, Shuai Meng, Xiaodan Gong, Zhaohui Ye, Meng Wang, Shuyun Wang, Chenji Gao, Kun |
author_sort | Jin, Xiaofeng |
collection | PubMed |
description | Speckle-type Poz protein (SPOP), an E3 ubiquitin ligase adaptor, is the most frequently mutated gene in prostate cancer. The SPOP-mutated subtype of prostate cancer shows high genomic instability, but the underlying mechanisms causing this phenotype are still largely unknown. Here, we report that upon DNA damage, SPOP is phosphorylated at Ser119 by the ATM serine/threonine kinase, which potentiates the binding of SPOP to homeodomain-interacting protein kinase 2 (HIPK2), resulting in a nondegradative ubiquitination of HIPK2. This modification subsequently increases the phosphorylation activity of HIPK2 toward HP1γ, and then promotes the dissociation of HP1γ from trimethylated (Lys9) histone H3 (H3K9me3) to initiate DNA damage repair. Moreover, the effect of SPOP on the HIPK2-HP1γ axis is abrogated by prostate cancer-associated SPOP mutations. Our findings provide new insights into the molecular mechanism of SPOP mutations-driven genomic instability in prostate cancer. |
format | Online Article Text |
id | pubmed-8266658 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-82666582021-07-09 Prostate cancer-associated SPOP mutations lead to genomic instability through disruption of the SPOP–HIPK2 axis Jin, Xiaofeng Qing, Shi Li, Qian Zhuang, Hui Shen, Liliang Li, Jinhui Qi, Honggang Lin, Ting Lin, Zihan Wang, Jian Cao, Xinyi Yang, Jianye Ma, Qi Cong, Linghua Xi, Yang Fang, Shuai Meng, Xiaodan Gong, Zhaohui Ye, Meng Wang, Shuyun Wang, Chenji Gao, Kun Nucleic Acids Res Genome Integrity, Repair and Replication Speckle-type Poz protein (SPOP), an E3 ubiquitin ligase adaptor, is the most frequently mutated gene in prostate cancer. The SPOP-mutated subtype of prostate cancer shows high genomic instability, but the underlying mechanisms causing this phenotype are still largely unknown. Here, we report that upon DNA damage, SPOP is phosphorylated at Ser119 by the ATM serine/threonine kinase, which potentiates the binding of SPOP to homeodomain-interacting protein kinase 2 (HIPK2), resulting in a nondegradative ubiquitination of HIPK2. This modification subsequently increases the phosphorylation activity of HIPK2 toward HP1γ, and then promotes the dissociation of HP1γ from trimethylated (Lys9) histone H3 (H3K9me3) to initiate DNA damage repair. Moreover, the effect of SPOP on the HIPK2-HP1γ axis is abrogated by prostate cancer-associated SPOP mutations. Our findings provide new insights into the molecular mechanism of SPOP mutations-driven genomic instability in prostate cancer. Oxford University Press 2021-06-16 /pmc/articles/PMC8266658/ /pubmed/34133717 http://dx.doi.org/10.1093/nar/gkab489 Text en © The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Genome Integrity, Repair and Replication Jin, Xiaofeng Qing, Shi Li, Qian Zhuang, Hui Shen, Liliang Li, Jinhui Qi, Honggang Lin, Ting Lin, Zihan Wang, Jian Cao, Xinyi Yang, Jianye Ma, Qi Cong, Linghua Xi, Yang Fang, Shuai Meng, Xiaodan Gong, Zhaohui Ye, Meng Wang, Shuyun Wang, Chenji Gao, Kun Prostate cancer-associated SPOP mutations lead to genomic instability through disruption of the SPOP–HIPK2 axis |
title | Prostate cancer-associated SPOP mutations lead to genomic instability through disruption of the SPOP–HIPK2 axis |
title_full | Prostate cancer-associated SPOP mutations lead to genomic instability through disruption of the SPOP–HIPK2 axis |
title_fullStr | Prostate cancer-associated SPOP mutations lead to genomic instability through disruption of the SPOP–HIPK2 axis |
title_full_unstemmed | Prostate cancer-associated SPOP mutations lead to genomic instability through disruption of the SPOP–HIPK2 axis |
title_short | Prostate cancer-associated SPOP mutations lead to genomic instability through disruption of the SPOP–HIPK2 axis |
title_sort | prostate cancer-associated spop mutations lead to genomic instability through disruption of the spop–hipk2 axis |
topic | Genome Integrity, Repair and Replication |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266658/ https://www.ncbi.nlm.nih.gov/pubmed/34133717 http://dx.doi.org/10.1093/nar/gkab489 |
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