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C16orf72/HAPSTR1/TAPR1 functions with BRCA1/Senataxin to modulate replication-associated R-loops and confer resistance to PARP disruption

Author

Listed:
  • Abhishek Bharadwaj Sharma

    (University of Oxford)

  • Muhammad Khairul Ramlee

    (University of Oxford)

  • Joel Kosmin

    (University of Oxford)

  • Martin R. Higgs

    (University of Birmingham)

  • Amy Wolstenholme

    (University of Oxford)

  • George E. Ronson

    (University of Oxford
    University of Birmingham)

  • Dylan Jones

    (University of Oxford)

  • Daniel Ebner

    (University of Oxford)

  • Noor Shamkhi

    (University of Oxford)

  • David Sims

    (University of Oxford, John Radcliffe Hospital)

  • Paul W. G. Wijnhoven

    (Early Oncology R&D, AstraZeneca, 1 Francis Crick Avenue, Cambridge Biomedical Campus)

  • Josep V. Forment

    (Early Oncology R&D, AstraZeneca, 1 Francis Crick Avenue, Cambridge Biomedical Campus)

  • Ian Gibbs-Seymour

    (University of Oxford)

  • Nicholas D. Lakin

    (University of Oxford)

Abstract

While the toxicity of PARP inhibitors to cells with defects in homologous recombination (HR) is well established, other synthetic lethal interactions with PARP1/PARP2 disruption are poorly defined. To inform on these mechanisms we conducted a genome-wide screen for genes that are synthetic lethal with PARP1/2 gene disruption and identified C16orf72/HAPSTR1/TAPR1 as a novel modulator of replication-associated R-loops. C16orf72 is critical to facilitate replication fork restart, suppress DNA damage and maintain genome stability in response to replication stress. Importantly, C16orf72 and PARP1/2 function in parallel pathways to suppress DNA:RNA hybrids that accumulate at stalled replication forks. Mechanistically, this is achieved through an interaction of C16orf72 with BRCA1 and the RNA/DNA helicase Senataxin to facilitate their recruitment to RNA:DNA hybrids and confer resistance to PARP inhibitors. Together, this identifies a C16orf72/Senataxin/BRCA1-dependent pathway to suppress replication-associated R-loop accumulation, maintain genome stability and confer resistance to PARP inhibitors.

Suggested Citation

  • Abhishek Bharadwaj Sharma & Muhammad Khairul Ramlee & Joel Kosmin & Martin R. Higgs & Amy Wolstenholme & George E. Ronson & Dylan Jones & Daniel Ebner & Noor Shamkhi & David Sims & Paul W. G. Wijnhove, 2023. "C16orf72/HAPSTR1/TAPR1 functions with BRCA1/Senataxin to modulate replication-associated R-loops and confer resistance to PARP disruption," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40779-9
    DOI: 10.1038/s41467-023-40779-9
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    as
    1. Elodie Hatchi & Liana Goehring & Serena Landini & Konstantina Skourti-Stathaki & Derrick K. DeConti & Fieda O. Abderazzaq & Priyankana Banerjee & Timothy M. Demers & Yaoyu E. Wang & John Quackenbush &, 2021. "BRCA1 and RNAi factors promote repair mediated by small RNAs and PALB2–RAD52," Nature, Nature, vol. 591(7851), pages 665-670, March.
    2. Michal Zimmermann & Olga Murina & Martin A. M. Reijns & Angelo Agathanggelou & Rachel Challis & Žygimantė Tarnauskaitė & Morwenna Muir & Adeline Fluteau & Michael Aregger & Andrea McEwan & Wei Yuan & , 2018. "CRISPR screens identify genomic ribonucleotides as a source of PARP-trapping lesions," Nature, Nature, vol. 559(7713), pages 285-289, July.
    3. Charles Bou-Nader & Ankur Bothra & David N. Garboczi & Stephen H. Leppla & Jinwei Zhang, 2022. "Structural basis of R-loop recognition by the S9.6 monoclonal antibody," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    4. Mateusz Jurga & Arwa A. Abugable & Alastair S. H. Goldman & Sherif F. El-Khamisy, 2021. "USP11 controls R-loops by regulating senataxin proteostasis," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    5. Sarah Cohen & Nadine Puget & Yea-Lih Lin & Thomas Clouaire & Marion Aguirrebengoa & Vincent Rocher & Philippe Pasero & Yvan Canitrot & Gaëlle Legube, 2018. "Senataxin resolves RNA:DNA hybrids forming at DNA double-strand breaks to prevent translocations," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    6. Xiaowen Zhang & Huai-Chin Chiang & Yao Wang & Chi Zhang & Sabrina Smith & Xiayan Zhao & Sreejith J. Nair & Joel Michalek & Ismail Jatoi & Meeghan Lautner & Boyce Oliver & Howard Wang & Anna Petit & Te, 2017. "Attenuation of RNA polymerase II pausing mitigates BRCA1-associated R-loop accumulation and tumorigenesis," Nature Communications, Nature, vol. 8(1), pages 1-12, August.
    7. George E. Ronson & Ann Liza Piberger & Martin R. Higgs & Anna L. Olsen & Grant S. Stewart & Peter J. McHugh & Eva Petermann & Nicholas D. Lakin, 2018. "PARP1 and PARP2 stabilise replication forks at base excision repair intermediates through Fbh1-dependent Rad51 regulation," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    8. Jirina Bartkova & Zuzana Hořejší & Karen Koed & Alwin Krämer & Frederic Tort & Karsten Zieger & Per Guldberg & Maxwell Sehested & Jahn M. Nesland & Claudia Lukas & Torben Ørntoft & Jiri Lukas & Jiri B, 2005. "DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis," Nature, Nature, vol. 434(7035), pages 864-870, April.
    9. Shaliny Ramachandran & Tiffany S. Ma & Jon Griffin & Natalie Ng & Iosifina P. Foskolou & Ming-Shih Hwang & Pedro Victori & Wei-Chen Cheng & Francesca M. Buffa & Katarzyna B. Leszczynska & Sherif F. El, 2021. "Hypoxia-induced SETX links replication stress with the unfolded protein response," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    10. Hannah Farmer & Nuala McCabe & Christopher J. Lord & Andrew N. J. Tutt & Damian A. Johnson & Tobias B. Richardson & Manuela Santarosa & Krystyna J. Dillon & Ian Hickson & Charlotte Knights & Niall M. , 2005. "Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy," Nature, Nature, vol. 434(7035), pages 917-921, April.
    11. Yaqun Teng & Tribhuwan Yadav & Meihan Duan & Jun Tan & Yufei Xiang & Boya Gao & Jianquan Xu & Zhuobin Liang & Yang Liu & Satoshi Nakajima & Yi Shi & Arthur S. Levine & Lee Zou & Li Lan, 2018. "ROS-induced R loops trigger a transcription-coupled but BRCA1/2-independent homologous recombination pathway through CSB," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    12. Prasun Chakraborty & Kevin Hiom, 2021. "DHX9-dependent recruitment of BRCA1 to RNA promotes DNA end resection in homologous recombination," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
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