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HP1β Chromo Shadow Domain facilitates H2A ubiquitination for BRCA1 recruitment at DNA double-strand breaks

Vijaya Charaka, Sharmista Chakraborty, Chi-Lin Tsai, Xiaoyan Wang, Raj K Pandita, John A. Tainer, Clayton R Hunt, View ORCID ProfileTej K. Pandita
doi: https://doi.org/10.1101/2022.01.11.475809
Vijaya Charaka
1Department of Radiation Oncology, The Houston Methodist Research Institute, Houston TX 77030, USA
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Sharmista Chakraborty
1Department of Radiation Oncology, The Houston Methodist Research Institute, Houston TX 77030, USA
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Chi-Lin Tsai
2Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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Xiaoyan Wang
2Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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Raj K Pandita
1Department of Radiation Oncology, The Houston Methodist Research Institute, Houston TX 77030, USA
3Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
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John A. Tainer
2Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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Clayton R Hunt
1Department of Radiation Oncology, The Houston Methodist Research Institute, Houston TX 77030, USA
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Tej K. Pandita
1Department of Radiation Oncology, The Houston Methodist Research Institute, Houston TX 77030, USA
3Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
4Center for Genomics and Precision Medicine, Texas A&M College of Medicine, Houston, Texas, USA
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  • ORCID record for Tej K. Pandita
  • For correspondence: tejkrishnanpandita@gmail.com
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Abstract

Efficient DNA double strand break (DSB) repair by homologous recombination (HR), as orchestrated by histone and non-histone proteins, is critical to genome stability, replication, transcription, and cancer avoidance. Here we report that Heterochromatin Protein1 beta (HP1β) acts as a key component of the HR DNA resection step by regulating BRCA1 enrichment at DNA damage sites, a function largely dependent on the HP1β chromo shadow domain (CSD). HP1β itself is enriched at DSBs within gene-rich regions through a CSD interaction with Chromatin Assembly Factor 1 (CAF1) and HP1 β depletion impairs subsequent BRCA1 enrichment. An added interaction of the HP1 β CSD with the Polycomb Repressor Complex 1 ubiquitinase component RING1A facilitates BRCA1 recruitment by increasing H2A lysine 118-119 ubiquitination, a marker for BRCA1 recruitment. Our findings reveal that HP1β interactions, mediated through its CSD with RING1A, promote H2A ubiquitination and facilitate BRCA1 recruitment at DNA damage sites, a critical step in DSB repair by the HR pathway. These collective results unveil how HP1β is recruited to DSBs in gene-rich regions and how HP1β subsequently promotes BRCA1 recruitment to further HR DNA damage repair by stimulating CtIP-dependent resection.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Authors e-mail address: Vijay K. Charaka: vkcharaka{at}houstonmethodist.org

    Sharmistha Chakraborty: sharmisthachakraborty70{at}gmail.com

    Chi Lin Tsai: ctsai5{at}mdanderson.org

    Xiaoyan Wang: xiaoyan.wang2016{at}outlook.com

    Raj K. Pandita: rkp_jalali{at}yahoo.com

    John A. Tainer: jtainer{at}mdanderson.org

    Clayton R Hunt: crhunt305{at}gmail.com

    Tej K. Pandita: tejkrishnanpandita{at}gmail.com; tej.pandita{at}BCM.edu; tpandita{at}tamu.edu

  • Authors have no conflict of interest

Copyright 
The copyright holder has placed this preprint in the Public Domain. It is no longer restricted by copyright. Anyone can legally share, reuse, remix, or adapt this material for any purpose without crediting the original authors.
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Posted January 11, 2022.
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HP1β Chromo Shadow Domain facilitates H2A ubiquitination for BRCA1 recruitment at DNA double-strand breaks
Vijaya Charaka, Sharmista Chakraborty, Chi-Lin Tsai, Xiaoyan Wang, Raj K Pandita, John A. Tainer, Clayton R Hunt, Tej K. Pandita
bioRxiv 2022.01.11.475809; doi: https://doi.org/10.1101/2022.01.11.475809
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HP1β Chromo Shadow Domain facilitates H2A ubiquitination for BRCA1 recruitment at DNA double-strand breaks
Vijaya Charaka, Sharmista Chakraborty, Chi-Lin Tsai, Xiaoyan Wang, Raj K Pandita, John A. Tainer, Clayton R Hunt, Tej K. Pandita
bioRxiv 2022.01.11.475809; doi: https://doi.org/10.1101/2022.01.11.475809

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