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HJURP is recruited to double-strand break sites and facilitates DNA repair by promoting chromatin reorganization

Oncogene volume 43, pages 804–820 (2024)Cite this article

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Abstract

HJURP is overexpressed in several cancer types and strongly correlates with patient survival. However, the mechanistic basis underlying the association of HJURP with cancer aggressiveness is not well understood. HJURP promotes the loading of the histone H3 variant, CENP-A, at the centromeric chromatin, epigenetically defining the centromeres and supporting proper chromosome segregation. In addition, HJURP is associated with DNA repair but its function in this process is still scarcely explored. Here, we demonstrate that HJURP is recruited to DSBs through a mechanism requiring chromatin PARylation and promotes epigenetic alterations that favor the execution of DNA repair. Incorporation of HJURP at DSBs promotes turnover of H3K9me3 and HP1, facilitating DNA damage signaling and DSB repair. Moreover, HJURP overexpression in glioma cell lines also affected global structure of heterochromatin independently of DNA damage induction, promoting genome-wide reorganization and assisting DNA damage response. HJURP overexpression therefore extensively alters DNA damage signaling and DSB repair, and also increases radioresistance of glioma cells. Importantly, HJURP expression levels in tumors are also associated with poor response of patients to radiation. Thus, our results enlarge the understanding of HJURP involvement in DNA repair and highlight it as a promising target for the development of adjuvant therapies that sensitize tumor cells to irradiation.

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Fig. 1: HJURP is recruited to DNA damage sites.
Fig. 2: HJURP is required for DSB repair.
Fig. 3: HJURP promotes chromatin relaxation.
Fig. 4: HJURP depletion increases H3K9me3 occupancy in heterochromatic regions.
Fig. 5: HJURP suppression affects global chromatin structure and limits DNA damage signaling.
Fig. 6: HJURP overexpression correlates with radioresistance.
Fig. 7: Proposed model for the role of HJURP in regulating chromatin accessibility at DSBs.

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Data availability

Further information and requests for resources and reagents should be directed to and will be fulfilled by the lead contact, VV (valeria.valente@unesp.br).

Materials availability

All genetic modified cell lines generated in this study are available from the lead contact.

Code availability

The standardized datasets produced in this manuscript were deposited in the Bioproject (NCBI). Access code is PRJNA855124. The code developed for the analysis of ChIPseq data can be accessed in the link: https://github.com/arnopenzias/ChIP-seq.git.

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Acknowledgements

The authors thank Silvia Regina Andrade Nascimento and Chelsea Carman for technical assistance, Juliana Ferreira de Sousa for siHJURP#2 design, and Carlos Gilberto Carlotti, Elza Tiemi Sakamoto Hojo and Michael Bobola for gently providing cell lines. We also make a special acknowledgment to Mariana Santos de Queiroz for the helpful technical assistance in cloning experiments. RBS and GN were supported by CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior), and CC by CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico).

Funding

This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (grants #2013/13465-1, #2018/05018-9 and #2022/09066-3 to VV; grant #2013/08135-2 to WASJ; and grants #2014/18189-5 and #2021/10032-3 to EME), Programa de Apoio ao Desenvolvimento Científico (PADC) from the Faculty of Pharmaceutical Sciences of Araraquara - UNESP, Conselho Nacional de Desenvolvimento Científico e Tecnológico (#312249/2019-5 to EME) and the National Institutes of Health (NIH) (grants CA177804 and CA93602 to BDP). This study was also financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001.

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Author notes

  1. These authors jointly supervised this work: Brendan D. Price, Valeria Valente.

Authors and Affiliations

  1. Department of Cellular and Molecular Biology, Ribeirão Preto Medical School, University of São Paulo (USP), Avenida Bandeirantes, 3900, Ribeirão Preto, 14049-900, Brazil

    Rodolfo B. Serafim, Cibele Cardoso, Enilza M. Espreafico, Maria L. Paçó-Larson & Valeria Valente

  2. São Paulo State University (UNESP), School of Pharmaceutical Sciences, Rodovia Araraquara - Jaú, Km 01 - s/n, Campos Ville, Araraquara, SP, 14800-903, Brazil

    Rodolfo B. Serafim, Geovana Navegante & Valeria Valente

  3. Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA

    Rodolfo B. Serafim, Hongyun Qi, Ramya Parasuram & Brendan D. Price

  4. Center for Cell-Based Therapy-CEPID/FAPESP, Rua Tenente Catão Roxo, 2501, Ribeirão Preto, 14051-140, Brazil

    Rodolfo B. Serafim, Cibele Cardoso, Wilson A. Silva Jr & Valeria Valente

  5. Department of Genetics, Ribeirão Preto Medical School, University of São Paulo (USP), Avenida Bandeirantes, 3900, Ribeirão Preto, 14049-900, Brazil

    Cibele Cardoso, Camila B. Storti & Wilson A. Silva Jr

  6. Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil

    Patrick da Silva & Jean Pierre S. Peron

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  1. Rodolfo B. Serafim
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Contributions

Investigation, RBS, CC, CBS, PS, HQ, RP and GN; Formal Analysis, RBS; Conceptualization, RBS, BDP and VV; Writing – original draft, RBS, BDP and VV; Writing – Review & Editing; BDP and VV; Funding Acquisition, BDP and VV; Supervision, BDP and VV; Resources, JPSP, WASJ, EME, MLPL, BDP and VV.

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Correspondence to Brendan D. Price or Valeria Valente.

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Serafim, R.B., Cardoso, C., Storti, C.B. et al. HJURP is recruited to double-strand break sites and facilitates DNA repair by promoting chromatin reorganization. Oncogene 43, 804–820 (2024). https://doi.org/10.1038/s41388-024-02937-1

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