The HDAC6-RNF168 axis regulates H2A/H2A.X ubiquitination to enable double-strand break repair

Histone deacetylase 6 (HDAC6) mediates DNA damage signaling by regulating the mismatch repair and nucleotide excision repair pathways. Whether HDAC6 also mediates DNA double-strand break (DSB) repair is unclear. Here, we report that HDAC6 negatively regulates DSB repair in an enzyme activity-indepen...

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Autores principales: Qiu, Lingyu, Xu, Wenchao, Lu, Xiaopeng, Chen, Feng, Chen, Yongcan, Tian, Yuan, Zhu, Qian, Liu, Xiangyu, Wang, Yongqing, Pei, Xin-Hai, Xu, Xingzhi, Zhang, Jun, Zhu, Wei-Guo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2023
Materias:
Genome Integrity, Repair and Replication
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10516627/
https://www.ncbi.nlm.nih.gov/pubmed/37503842
http://dx.doi.org/10.1093/nar/gkad631
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author Qiu, Lingyu
Xu, Wenchao
Lu, Xiaopeng
Chen, Feng
Chen, Yongcan
Tian, Yuan
Zhu, Qian
Liu, Xiangyu
Wang, Yongqing
Pei, Xin-Hai
Xu, Xingzhi
Zhang, Jun
Zhu, Wei-Guo
author_facet Qiu, Lingyu
Xu, Wenchao
Lu, Xiaopeng
Chen, Feng
Chen, Yongcan
Tian, Yuan
Zhu, Qian
Liu, Xiangyu
Wang, Yongqing
Pei, Xin-Hai
Xu, Xingzhi
Zhang, Jun
Zhu, Wei-Guo
author_sort Qiu, Lingyu
collection PubMed
description Histone deacetylase 6 (HDAC6) mediates DNA damage signaling by regulating the mismatch repair and nucleotide excision repair pathways. Whether HDAC6 also mediates DNA double-strand break (DSB) repair is unclear. Here, we report that HDAC6 negatively regulates DSB repair in an enzyme activity-independent manner. In unstressed cells, HDAC6 interacts with H2A/H2A.X to prevent its interaction with the E3 ligase RNF168. Upon sensing DSBs, RNF168 rapidly ubiquitinates HDAC6 at lysine 116, leading to HDAC6 proteasomal degradation and a restored interaction between RNF168 and H2A/H2A.X. H2A/H2A.X is ubiquitinated by RNF168, precipitating the recruitment of DSB repair factors (including 53BP1 and BRCA1) to chromatin and subsequent DNA repair. These findings reveal novel regulatory machinery based on an HDAC6–RNF168 axis that regulates the H2A/H2A.X ubiquitination status. Interfering with this axis might be leveraged to disrupt a key mechanism of cancer cell resistance to genotoxic damage and form a potential therapeutic strategy for cancer.
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spelling pubmed-105166272023-09-23 The HDAC6-RNF168 axis regulates H2A/H2A.X ubiquitination to enable double-strand break repair Qiu, Lingyu Xu, Wenchao Lu, Xiaopeng Chen, Feng Chen, Yongcan Tian, Yuan Zhu, Qian Liu, Xiangyu Wang, Yongqing Pei, Xin-Hai Xu, Xingzhi Zhang, Jun Zhu, Wei-Guo Nucleic Acids Res Genome Integrity, Repair and Replication Histone deacetylase 6 (HDAC6) mediates DNA damage signaling by regulating the mismatch repair and nucleotide excision repair pathways. Whether HDAC6 also mediates DNA double-strand break (DSB) repair is unclear. Here, we report that HDAC6 negatively regulates DSB repair in an enzyme activity-independent manner. In unstressed cells, HDAC6 interacts with H2A/H2A.X to prevent its interaction with the E3 ligase RNF168. Upon sensing DSBs, RNF168 rapidly ubiquitinates HDAC6 at lysine 116, leading to HDAC6 proteasomal degradation and a restored interaction between RNF168 and H2A/H2A.X. H2A/H2A.X is ubiquitinated by RNF168, precipitating the recruitment of DSB repair factors (including 53BP1 and BRCA1) to chromatin and subsequent DNA repair. These findings reveal novel regulatory machinery based on an HDAC6–RNF168 axis that regulates the H2A/H2A.X ubiquitination status. Interfering with this axis might be leveraged to disrupt a key mechanism of cancer cell resistance to genotoxic damage and form a potential therapeutic strategy for cancer. Oxford University Press 2023-07-28 /pmc/articles/PMC10516627/ /pubmed/37503842 http://dx.doi.org/10.1093/nar/gkad631 Text en © The Author(s) 2023. 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 (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
Qiu, Lingyu
Xu, Wenchao
Lu, Xiaopeng
Chen, Feng
Chen, Yongcan
Tian, Yuan
Zhu, Qian
Liu, Xiangyu
Wang, Yongqing
Pei, Xin-Hai
Xu, Xingzhi
Zhang, Jun
Zhu, Wei-Guo
The HDAC6-RNF168 axis regulates H2A/H2A.X ubiquitination to enable double-strand break repair
title The HDAC6-RNF168 axis regulates H2A/H2A.X ubiquitination to enable double-strand break repair
title_full The HDAC6-RNF168 axis regulates H2A/H2A.X ubiquitination to enable double-strand break repair
title_fullStr The HDAC6-RNF168 axis regulates H2A/H2A.X ubiquitination to enable double-strand break repair
title_full_unstemmed The HDAC6-RNF168 axis regulates H2A/H2A.X ubiquitination to enable double-strand break repair
title_short The HDAC6-RNF168 axis regulates H2A/H2A.X ubiquitination to enable double-strand break repair
title_sort hdac6-rnf168 axis regulates h2a/h2a.x ubiquitination to enable double-strand break repair
topic Genome Integrity, Repair and Replication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10516627/
https://www.ncbi.nlm.nih.gov/pubmed/37503842
http://dx.doi.org/10.1093/nar/gkad631
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