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

被引：12
|
作者：
Qiu, Lingyu [1 ]
Xu, Wenchao [1 ]
Lu, Xiaopeng [1 ]
Chen, Feng [1 ]
Chen, Yongcan [1 ]
Tian, Yuan [1 ]
Zhu, Qian [1 ]
Liu, Xiangyu [1 ]
Wang, Yongqing [2 ]
Pei, Xin-Hai [3 ]
Xu, Xingzhi [4 ]
Zhang, Jun [1 ]
Zhu, Wei-Guo [1 ,5 ,6 ]
机构：
[1] Shenzhen Univ, Med Sch, Dept Biochem & Mol Biol, Int Canc Ctr,Guangdong Key Lab Genome Instabil &, Shenzhen 518055, Peoples R China
[2] Univ Toledo, Med Ctr, Div Rheumatol & Immunol, 3120 Glendale Ave, Toledo, OH 43614 USA
[3] Shenzhen Univ, Med Sch, Guangdong Key Lab Genome Instabil & Human Dis Pre, Marshall Lab Biomed Engn,Dept Anat & Histol, Shenzhen, 518055, Peoples R China
[4] Shenzhen Univ, Med Sch, Dept Cell Biol & Med Genet, Int Canc Ctr,Guangdong Key Lab Genome Instabil &, Shenzhen 518055, Peoples R China
[5] Wannan Med Coll, Sch Basic Med Sci, Wuhu 241002, Anhui, Peoples R China
[6] Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci, Dept Biochem & Biophys, Beijing 100191, Peoples R China
来源：
NUCLEIC ACIDS RESEARCH | 2023年 / 51卷 / 17期
基金：
中国国家自然科学基金;
关键词：
DNA-DAMAGE RESPONSE; HISTONE UBIQUITINATION; RNF168; UBIQUITYLATION; 53BP1; RNF8; H2AX; PHOSPHORYLATION; POLYUBIQUITIN; ACETYLATION;
D O I：
10.1093/nar/gkad631
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
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.
引用
收藏
页码：9166 / 9182
页数：17
相关论文
共 50 条
  • [1] Histone H2A phosphorylation in DNA double-strand break repair
    Foster, ER
    Downs, JA
    FEBS JOURNAL, 2005, 272 (13) : 3231 - 3240
  • [2] Histone H2A modifications distinguish pathways of double-strand break repair
    不详
    BIOCHEMISTRY AND CELL BIOLOGY-BIOCHIMIE ET BIOLOGIE CELLULAIRE, 2005, 83 (04): : 570 - 570
  • [3] Ubiquitinated H2A.X-Induced RNF168 Condensation Promotes DNA Double-Strand Break Repair and Tumor Radioresistance
    Feng, L. L.
    Bie, S. Y.
    Wan, X.
    Fan, X.
    Wang, Y. L.
    INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS, 2023, 117 (02): : E266 - E267
  • [4] RNF168-mediated H2A neddylation antagonizes ubiquitylation of H2A and regulates DNA damage repair
    Li, Tingting
    Guan, Junhong
    Huang, Ziji
    Hu, Xiang
    Zheng, Xiaofeng
    JOURNAL OF CELL SCIENCE, 2014, 127 (10) : 2238 - 2248
  • [5] RNF20-SNF2H Pathway of Chromatin Relaxation in DNA Double-Strand Break Repair
    Kato, Akihiro
    Komatsu, Kenshi
    GENES, 2015, 6 (03): : 592 - 606
  • [6] Dynamics of yeast histone H2A and H2B phosphorylation in response to a double-strand break
    Cheng-Sheng Lee
    Kihoon Lee
    Gaëlle Legube
    James E Haber
    Nature Structural & Molecular Biology, 2014, 21 : 103 - 109
  • [7] Dynamics of yeast histone H2A and H2B phosphorylation in response to a double-strand break
    Lee, Cheng-Sheng
    Lee, Kihoon
    Legube, Gaelle
    Haber, James E.
    NATURE STRUCTURAL & MOLECULAR BIOLOGY, 2014, 21 (01) : 103 - +
  • [8] Dynamics of Yeast Histone H2A and H2B Phosphorylation in Response to a Double-Strand Break
    Lee, Cheng-Sheng
    Lee, Kihoon
    Haber, James E.
    Legube, Gaelle
    FASEB JOURNAL, 2013, 27
  • [9] The γ-H2A.X:: Is it just a surrogate marker of double-strand breaks or much more?
    Ismail, Ismail Hassan
    Hendzel, Michael J.
    ENVIRONMENTAL AND MOLECULAR MUTAGENESIS, 2008, 49 (01) : 73 - 82
  • [10] Assessing Candidate Gene nsSNPs for Phenotypic Differences in Double-Strand Break Repair Using Radiation-Induced gamma H2A.X Foci
    Markunas, Christina A.
    Umbach, David M.
    Xu, Zongli
    Taylor, Jack A.
    JOURNAL OF CANCER EPIDEMIOLOGY, 2008, 2008
12345