IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v12y2021i1d10.1038_s41467-021-27284-7.html
   My bibliography  Save this article

Structural evolution of a DNA repair self-resistance mechanism targeting genotoxic secondary metabolites

Author

Listed:
  • Elwood A. Mullins

    (Vanderbilt University)

  • Jonathan Dorival

    (Vanderbilt University)

  • Gong-Li Tang

    (Chinese Academy of Sciences)

  • Dale L. Boger

    (The Scripps Research Institute)

  • Brandt F. Eichman

    (Vanderbilt University
    Vanderbilt University School of Medicine)

Abstract

Microbes produce a broad spectrum of antibiotic natural products, including many DNA-damaging genotoxins. Among the most potent of these are DNA alkylating agents in the spirocyclopropylcyclohexadienone (SCPCHD) family, which includes the duocarmycins, CC-1065, gilvusmycin, and yatakemycin. The yatakemycin biosynthesis cluster in Streptomyces sp. TP-A0356 contains an AlkD-related DNA glycosylase, YtkR2, that serves as a self-resistance mechanism against yatakemycin toxicity. We previously reported that AlkD, which is not present in an SCPCHD producer, provides only limited resistance against yatakemycin. We now show that YtkR2 and C10R5, a previously uncharacterized homolog found in the CC-1065 biosynthetic gene cluster of Streptomyces zelensis, confer far greater resistance against their respective SCPCHD natural products. We identify a structural basis for substrate specificity across gene clusters and show a correlation between in vivo resistance and in vitro enzymatic activity indicating that reduced product affinity—not enhanced substrate recognition—is the evolutionary outcome of selective pressure to provide self-resistance against yatakemycin and CC-1065.

Suggested Citation

  • Elwood A. Mullins & Jonathan Dorival & Gong-Li Tang & Dale L. Boger & Brandt F. Eichman, 2021. "Structural evolution of a DNA repair self-resistance mechanism targeting genotoxic secondary metabolites," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27284-7
    DOI: 10.1038/s41467-021-27284-7
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-021-27284-7
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-021-27284-7?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. Elwood A. Mullins & Rongxin Shi & Zachary D. Parsons & Philip K. Yuen & Sheila S. David & Yasuhiro Igarashi & Brandt F. Eichman, 2015. "The DNA glycosylase AlkD uses a non-base-flipping mechanism to excise bulky lesions," Nature, Nature, vol. 527(7577), pages 254-258, November.
    2. Emily H. Rubinson & A. S. Prakasha Gowda & Thomas E. Spratt & Barry Gold & Brandt F. Eichman, 2010. "An unprecedented nucleic acid capture mechanism for excision of DNA damage," Nature, Nature, vol. 468(7322), pages 406-411, November.
    3. Ofer Fridman & Amir Goldberg & Irine Ronin & Noam Shoresh & Nathalie Q. Balaban, 2014. "Optimization of lag time underlies antibiotic tolerance in evolved bacterial populations," Nature, Nature, vol. 513(7518), pages 418-421, September.
    4. Hua Yuan & Jinru Zhang & Yujuan Cai & Sheng Wu & Kui Yang & H. C. Stephen Chan & Wei Huang & Wen-Bing Jin & Yan Li & Yue Yin & Yasuhiro Igarashi & Shuguang Yuan & Jiahai Zhou & Gong-Li Tang, 2017. "GyrI-like proteins catalyze cyclopropanoid hydrolysis to confer cellular protection," Nature Communications, Nature, vol. 8(1), pages 1-8, December.
    5. Tai L. Ng & Roman Rohac & Andrew J. Mitchell & Amie K. Boal & Emily P. Balskus, 2019. "An N-nitrosating metalloenzyme constructs the pharmacophore of streptozotocin," Nature, Nature, vol. 566(7742), pages 94-99, February.
    6. Stephen P. Jackson & Jiri Bartek, 2009. "The DNA-damage response in human biology and disease," Nature, Nature, vol. 461(7267), pages 1071-1078, October.
    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. Zita Gál & Stavroula Boukoura & Kezia Catharina Oxe & Sara Badawi & Blanca Nieto & Lea Milling Korsholm & Sille Blangstrup Geisler & Ekaterina Dulina & Anna Vestergaard Rasmussen & Christina Dahl & We, 2024. "Hyper-recombination in ribosomal DNA is driven by long-range resection-independent RAD51 accumulation," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    2. Ilaria Rosso & Corey Jones-Weinert & Francesca Rossiello & Matteo Cabrini & Silvia Brambillasca & Leonel Munoz-Sagredo & Zeno Lavagnino & Emanuele Martini & Enzo Tedone & Massimiliano Garre’ & Julio A, 2023. "Alternative lengthening of telomeres (ALT) cells viability is dependent on C-rich telomeric RNAs," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    3. Halh Al-Serori & Franziska Ferk & Michael Kundi & Andrea Bileck & Christopher Gerner & Miroslav Mišík & Armen Nersesyan & Monika Waldherr & Manuel Murbach & Tamara T Lah & Christel Herold-Mende & Andr, 2018. "Mobile phone specific electromagnetic fields induce transient DNA damage and nucleotide excision repair in serum-deprived human glioblastoma cells," PLOS ONE, Public Library of Science, vol. 13(4), pages 1-17, April.
    4. Daipayan Banerjee & Kurt Langberg & Salar Abbas & Eric Odermatt & Praveen Yerramothu & Martin Volaric & Matthew A. Reidenbach & Kathy J. Krentz & C. Dustin Rubinstein & David L. Brautigan & Tarek Abba, 2021. "A non-canonical, interferon-independent signaling activity of cGAMP triggers DNA damage response signaling," Nature Communications, Nature, vol. 12(1), pages 1-24, December.
    5. Marianne Bauer & Isabella R Graf & Vudtiwat Ngampruetikorn & Greg J Stephens & Erwin Frey, 2017. "Exploiting ecology in drug pulse sequences in favour of population reduction," PLOS Computational Biology, Public Library of Science, vol. 13(9), pages 1-17, September.
    6. Jenny Kaur Singh & Rebecca Smith & Magdalena B. Rother & Anton J. L. Groot & Wouter W. Wiegant & Kees Vreeken & Ostiane D’Augustin & Robbert Q. Kim & Haibin Qian & Przemek M. Krawczyk & Román González, 2021. "Zinc finger protein ZNF384 is an adaptor of Ku to DNA during classical non-homologous end-joining," Nature Communications, Nature, vol. 12(1), pages 1-21, December.
    7. Miho M. Suzuki & Kenta Iijima & Koichi Ogami & Keiko Shinjo & Yoshiteru Murofushi & Jingqi Xie & Xuebing Wang & Yotaro Kitano & Akira Mamiya & Yuji Kibe & Tatsunori Nishimura & Fumiharu Ohka & Ryuta S, 2023. "TUG1-mediated R-loop resolution at microsatellite loci as a prerequisite for cancer cell proliferation," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    8. Sourav Chowdhury & Daniel C. Zielinski & Christopher Dalldorf & Joao V. Rodrigues & Bernhard O. Palsson & Eugene I. Shakhnovich, 2023. "Empowering drug off-target discovery with metabolic and structural analysis," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    9. Ye Cai & Huifen Cao & Fang Wang & Yufei Zhang & Philipp Kapranov, 2022. "Complex genomic patterns of abasic sites in mammalian DNA revealed by a high-resolution SSiNGLe-AP method," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
    10. Sidrah Shah & Alison Cheung & Mikolaj Kutka & Matin Sheriff & Stergios Boussios, 2022. "Epithelial Ovarian Cancer: Providing Evidence of Predisposition Genes," IJERPH, MDPI, vol. 19(13), pages 1-14, July.
    11. Jérémy Sandoz & Max Cigrang & Amélie Zachayus & Philippe Catez & Lise-Marie Donnio & Clèmence Elly & Jadwiga Nieminuszczy & Pietro Berico & Cathy Braun & Sergey Alekseev & Jean-Marc Egly & Wojciech Ni, 2023. "Active mRNA degradation by EXD2 nuclease elicits recovery of transcription after genotoxic stress," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    12. Jessica D. Tischler & Hiroshi Tsuchida & Rosevalentine Bosire & Tommy T. Oda & Ana Park & Richard O. Adeyemi, 2024. "FLIP(C1orf112)-FIGNL1 complex regulates RAD51 chromatin association to promote viability after replication stress," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    13. Fei Sun & Nourhan Nashat Ali & Daniela Londoño-Vásquez & Constantine A. Simintiras & Huanyu Qiao & M. Sofia Ortega & Yuksel Agca & Masashi Takahashi & Rocío M. Rivera & Andrew M. Kelleher & Peter Suto, 2024. "Increased DNA damage in full-grown oocytes is correlated with diminished autophagy activation," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    14. Lin-Lin Zhou & Tao Zhang & Yun Xue & Chuan Yue & Yihui Pan & Pengyu Wang & Teng Yang & Meixia Li & Hu Zhou & Kan Ding & Jianhua Gan & Hongbin Ji & Cai-Guang Yang, 2023. "Selective activator of human ClpP triggers cell cycle arrest to inhibit lung squamous cell carcinoma," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    15. Daniel Gómez-Cabello & George Pappas & Diana Aguilar-Morante & Christoffel Dinant & Jiri Bartek, 2022. "CtIP-dependent nascent RNA expression flanking DNA breaks guides the choice of DNA repair pathway," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    16. Pedro Weickert & Hao-Yi Li & Maximilian J. Götz & Sophie Dürauer & Denitsa Yaneva & Shubo Zhao & Jacqueline Cordes & Aleida C. Acampora & Ignasi Forne & Axel Imhof & Julian Stingele, 2023. "SPRTN patient variants cause global-genome DNA-protein crosslink repair defects," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    17. Pradeep Ramalingam & Michael C. Gutkin & Michael G. Poulos & Taylor Tillery & Chelsea Doughty & Agatha Winiarski & Ana G. Freire & Shahin Rafii & David Redmond & Jason M. Butler, 2023. "Restoring bone marrow niche function rejuvenates aged hematopoietic stem cells by reactivating the DNA Damage Response," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    18. Ross J. Hill & Nazareno Bona & Job Smink & Hannah K. Webb & Alastair Crisp & Juan I. Garaycoechea & Gerry P. Crossan, 2024. "p53 regulates diverse tissue-specific outcomes to endogenous DNA damage in mice," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    19. Andrea M. Kaminski & Kishore K. Chiruvella & Dale A. Ramsden & Katarzyna Bebenek & Thomas A. Kunkel & Lars C. Pedersen, 2022. "Analysis of diverse double-strand break synapsis with Polλ reveals basis for unique substrate specificity in nonhomologous end-joining," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    20. Najmeh Soltanmohammadi & Siyao Wang & Björn Schumacher, 2022. "Somatic PMK-1/p38 signaling links environmental stress to germ cell apoptosis and heritable euploidy," Nature Communications, Nature, vol. 13(1), pages 1-13, 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:12:y:2021:i:1:d:10.1038_s41467-021-27284-7. 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.