IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-40779-9.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-40779-9
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-023-40779-9?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. 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.
    2. 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.
    3. 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.
    4. 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.
    5. 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.
    6. 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.
    7. 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.
    8. 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.
    9. 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.
    10. 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.
    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.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Takuya Tsujino & Tomoaki Takai & Kunihiko Hinohara & Fu Gui & Takeshi Tsutsumi & Xiao Bai & Chenkui Miao & Chao Feng & Bin Gui & Zsofia Sztupinszki & Antoine Simoneau & Ning Xie & Ladan Fazli & Xuesen, 2023. "CRISPR screens reveal genetic determinants of PARP inhibitor sensitivity and resistance in prostate cancer," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. Tomoko Yamamori Morita & Jie Yu & Yukie Kashima & Ryo Kamata & Gaku Yamamoto & Tatsunori Minamide & Chiaki Mashima & Miyuki Yoshiya & Yuta Sakae & Toyohiro Yamauchi & Yumi Hakozaki & Shun-ichiro Kagey, 2023. "CDC7 inhibition induces replication stress-mediated aneuploid cells with an inflammatory phenotype sensitizing tumors to immune checkpoint blockade," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    3. Zuzana Machacova & Katarina Chroma & David Lukac & Iva Protivankova & Pavel Moudry, 2024. "DNA polymerase α-primase facilitates PARP inhibitor-induced fork acceleration and protects BRCA1-deficient cells against ssDNA gaps," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    4. Xabier Vergara & Anna G. Manjón & Marcel Haas & Ben Morris & Ruben Schep & Christ Leemans & Anoek Friskes & Roderick L. Beijersbergen & Mathijs A. Sanders & René H. Medema & Bas Steensel, 2024. "Widespread chromatin context-dependencies of DNA double-strand break repair proteins," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    5. Neil J. Rzechorzek & Simone Kunzelmann & Andrew G. Purkiss & Mariana Silva Dos Santos & James I. MacRae & Ian A. Taylor & Kasper Fugger & Stephen C. West, 2023. "Mechanism of substrate hydrolysis by the human nucleotide pool sanitiser DNPH1," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    6. Susan Kilgas & Aleem Syed & Patrick Toolan-Kerr & Michelle L. Swift & Shrabasti Roychoudhury & Aniruddha Sarkar & Sarah Wilkins & Mikayla Quigley & Anna R. Poetsch & Maria Victoria Botuyan & Gaofeng C, 2024. "NEAT1 modulates the TIRR/53BP1 complex to maintain genome integrity," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    7. S. Cohen & A. Guenolé & I. Lazar & A. Marnef & T. Clouaire & D. V. Vernekar & N. Puget & V. Rocher & C. Arnould & M. Aguirrebengoa & M. Genais & N. Firmin & R. A. Shamanna & R. Mourad & V. A. Bohr & V, 2022. "A POLD3/BLM dependent pathway handles DSBs in transcribed chromatin upon excessive RNA:DNA hybrid accumulation," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    8. Xingxing Ren & Qiuyuan Liu & Peirong Zhou & Tingyue Zhou & Decai Wang & Qiao Mei & Richard A. Flavell & Zhanju Liu & Mingsong Li & Wen Pan & Shu Zhu, 2024. "DHX9 maintains epithelial homeostasis by restraining R-loop-mediated genomic instability in intestinal stem cells," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    9. Elias Einig & Chao Jin & Valentina Andrioletti & Boris Macek & Nikita Popov, 2023. "RNAPII-dependent ATM signaling at collisions with replication forks," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    10. Heathcliff Dorado García & Fabian Pusch & Yi Bei & Jennifer Stebut & Glorymar Ibáñez & Kristina Guillan & Koshi Imami & Dennis Gürgen & Jana Rolff & Konstantin Helmsauer & Stephanie Meyer-Liesener & N, 2022. "Therapeutic targeting of ATR in alveolar rhabdomyosarcoma," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    11. Sundarraj Jayakumar & Manthan Patel & Fanny Boulet & Hadicha Aziz & Greg N. Brooke & Hemanth Tummala & Madapura M. Pradeepa, 2024. "PSIP1/LEDGF reduces R-loops at transcription sites to maintain genome integrity," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    12. Megan E. Luedeman & Susanna Stroik & Wanjuan Feng & Adam J. Luthman & Gaorav P. Gupta & Dale A. Ramsden, 2022. "Poly(ADP) ribose polymerase promotes DNA polymerase theta-mediated end joining by activation of end resection," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    13. Yuxin Huang & Wenjing Li & Tzeh Foo & Jae-Hoon Ji & Bo Wu & Nozomi Tomimatsu & Qingming Fang & Boya Gao & Melissa Long & Jingfei Xu & Rouf Maqbool & Bipasha Mukherjee & Tengyang Ni & Salvador Alejo & , 2024. "DSS1 restrains BRCA2’s engagement with dsDNA for homologous recombination, replication fork protection, and R-loop homeostasis," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    14. Bing-Ze Yang & Mei-Yin Liu & Kuan-Lin Chiu & Yuh-Ling Chien & Ching-An Cheng & Yu-Lin Chen & Li-Yu Tsui & Keng-Ru Lin & Hsueh-Ping Catherine Chu & Ching-Shyi Peter Wu, 2024. "DHX9 SUMOylation is required for the suppression of R-loop-associated genome instability," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    15. Zizhi Tang & Ming Zeng & Xiaojun Wang & Chang Guo & Peng Yue & Xiaohu Zhang & Huiqiang Lou & Jun Chen & Dezhi Mu & Daochun Kong & Antony M. Carr & Cong Liu, 2022. "Synthetic lethality between TP53 and ENDOD1," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    16. Samuel D. Chauvin & Shoichiro Ando & Joe A. Holley & Atsushi Sugie & Fang R. Zhao & Subhajit Poddar & Rei Kato & Cathrine A. Miner & Yohei Nitta & Siddharth R. Krishnamurthy & Rie Saito & Yue Ning & Y, 2024. "Inherited C-terminal TREX1 variants disrupt homology-directed repair to cause senescence and DNA damage phenotypes in Drosophila, mice, and humans," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    17. Petra Brugge & Sarah C. Moser & Ivan Bièche & Petra Kristel & Sabrina Ibadioune & Alexandre Eeckhoutte & Roebi Bruijn & Eline Burg & Catrin Lutz & Stefano Annunziato & Julian Ruiter & Julien Masliah P, 2023. "Homologous recombination deficiency derived from whole-genome sequencing predicts platinum response in triple-negative breast cancers," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    18. Arindam Datta & Kajal Biswas & Joshua A. Sommers & Haley Thompson & Sanket Awate & Claudia M. Nicolae & Tanay Thakar & George-Lucian Moldovan & Robert H. Shoemaker & Shyam K. Sharan & Robert M. Brosh, 2021. "WRN helicase safeguards deprotected replication forks in BRCA2-mutated cancer cells," Nature Communications, Nature, vol. 12(1), pages 1-22, December.
    19. Meng Wang & Satoshi Fukushima & Yi-Shuan Sheen & Egle Ramelyte & Noel Cruz-Pacheco & Chenxu Shi & Shanshan Liu & Ishani Banik & Jamie D. Aquino & Martin Sangueza Acosta & Mitchell Levesque & Reinhard , 2024. "The genetic evolution of acral melanoma," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    20. Jun Dai & Shuyu Zheng & Matías M. Falco & Jie Bao & Johanna Eriksson & Sanna Pikkusaari & Sofia Forstén & Jing Jiang & Wenyu Wang & Luping Gao & Fernando Perez-Villatoro & Olli Dufva & Khalid Saeed & , 2024. "Tracing back primed resistance in cancer via sister cells," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40779-9. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.