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Genetic determinants of cellular addiction to DNA polymerase theta

Author

Listed:
  • Wanjuan Feng

    (University of North Carolina at Chapel Hill)

  • Dennis A. Simpson

    (University of North Carolina at Chapel Hill)

  • Juan Carvajal-Garcia

    (University of North Carolina at Chapel Hill)

  • Brandon A. Price

    (University of North Carolina at Chapel Hill)

  • Rashmi J. Kumar

    (University of North Carolina at Chapel Hill)

  • Lisle E. Mose

    (University of North Carolina at Chapel Hill)

  • Richard D. Wood

    (University of Texas MD Anderson Cancer Center)

  • Naim Rashid

    (University of North Carolina at Chapel Hill
    University of North Carolina at Chapel Hill)

  • Jeremy E. Purvis

    (University of North Carolina at Chapel Hill)

  • Joel S. Parker

    (University of North Carolina at Chapel Hill
    University of North Carolina at Chapel Hill)

  • Dale A. Ramsden

    (University of North Carolina at Chapel Hill
    University of North Carolina at Chapel Hill)

  • Gaorav P. Gupta

    (University of North Carolina at Chapel Hill
    University of North Carolina at Chapel Hill
    University of North Carolina at Chapel Hill)

Abstract

Polymerase theta (Pol θ, gene name Polq) is a widely conserved DNA polymerase that mediates a microhomology-mediated, error-prone, double strand break (DSB) repair pathway, referred to as Theta Mediated End Joining (TMEJ). Cells with homologous recombination deficiency are reliant on TMEJ for DSB repair. It is unknown whether deficiencies in other components of the DNA damage response (DDR) also result in Pol θ addiction. Here we use a CRISPR genetic screen to uncover 140 Polq synthetic lethal (PolqSL) genes, the majority of which were previously unknown. Functional analyses indicate that Pol θ/TMEJ addiction is associated with increased levels of replication-associated DSBs, regardless of the initial source of damage. We further demonstrate that approximately 30% of TCGA breast cancers have genetic alterations in PolqSL genes and exhibit genomic scars of Pol θ/TMEJ hyperactivity, thereby substantially expanding the subset of human cancers for which Pol θ inhibition represents a promising therapeutic strategy.

Suggested Citation

  • Wanjuan Feng & Dennis A. Simpson & Juan Carvajal-Garcia & Brandon A. Price & Rashmi J. Kumar & Lisle E. Mose & Richard D. Wood & Naim Rashid & Jeremy E. Purvis & Joel S. Parker & Dale A. Ramsden & Gao, 2019. "Genetic determinants of cellular addiction to DNA polymerase theta," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12234-1
    DOI: 10.1038/s41467-019-12234-1
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    Cited by:

    1. Anne Margriet Heijink & Colin Stok & David Porubsky & Eleni Maria Manolika & Jurrian K. Kanter & Yannick P. Kok & Marieke Everts & H. Rudolf Boer & Anastasia Audrey & Femke J. Bakker & Elles Wierenga , 2022. "Sister chromatid exchanges induced by perturbed replication can form independently of BRCA1, BRCA2 and RAD51," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Fumiaki Ito & Ziyuan Li & Leonid Minakhin & Gurushankar Chandramouly & Mrityunjay Tyagi & Robert Betsch & John J. Krais & Bernadette Taberi & Umeshkumar Vekariya & Marissa Calbert & Tomasz Skorski & N, 2024. "Structural basis for a Polθ helicase small-molecule inhibitor revealed by cryo-EM," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    3. Daniel J. Laverty & Shiv K. Gupta & Gary A. Bradshaw & Alexander S. Hunter & Brett L. Carlson & Nery Matias Calmo & Jiajia Chen & Shulan Tian & Jann N. Sarkaria & Zachary D. Nagel, 2024. "ATM inhibition exploits checkpoint defects and ATM-dependent double strand break repair in TP53-mutant glioblastoma," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    4. John J. Krais & David J. Glass & Ilse Chudoba & Yifan Wang & Wanjuan Feng & Dennis Simpson & Pooja Patel & Zemin Liu & Ryan Neumann-Domer & Robert G. Betsch & Andrea J. Bernhardy & Alice M. Bradbury &, 2023. "Genetic separation of Brca1 functions reveal mutation-dependent Polθ vulnerabilities," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    5. William Fried & Mrityunjay Tyagi & Leonid Minakhin & Gurushankar Chandramouly & Taylor Tredinnick & Mercy Ramanjulu & William Auerbacher & Marissa Calbert & Timur Rusanov & Trung Hoang & Nikita Boriso, 2024. "Discovery of a small-molecule inhibitor that traps Polθ on DNA and synergizes with PARP inhibitors," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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