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Structure-guided inhibition of the cancer DNA-mutating enzyme APOBEC3A

Author

Listed:
  • Stefan Harjes

    (Massey University)

  • Harikrishnan M. Kurup

    (Massey University)

  • Amanda E. Rieffer

    (University of Minnesota–Twin Cities)

  • Maitsetseg Bayarjargal

    (Massey University
    University of Washington)

  • Jana Filitcheva

    (Massey University)

  • Yongdong Su

    (Massey University
    Children’s Healthcare of Atlanta)

  • Tracy K. Hale

    (Massey University)

  • Vyacheslav V. Filichev

    (Massey University
    University of Auckland)

  • Elena Harjes

    (Massey University
    University of Auckland)

  • Reuben S. Harris

    (University of Texas Health San Antonio
    University of Texas Health San Antonio)

  • Geoffrey B. Jameson

    (Massey University
    University of Auckland)

Abstract

The normally antiviral enzyme APOBEC3A is an endogenous mutagen in human cancer. Its single-stranded DNA C-to-U editing activity results in multiple mutagenic outcomes including signature single-base substitution mutations (isolated and clustered), DNA breakage, and larger-scale chromosomal aberrations. APOBEC3A inhibitors may therefore comprise a unique class of anti-cancer agents that work by blocking mutagenesis, slowing tumor evolvability, and preventing detrimental outcomes such as drug resistance and metastasis. Here we reveal the structural basis of competitive inhibition of wildtype APOBEC3A by hairpin DNA bearing 2′-deoxy-5-fluorozebularine in place of the cytidine in the TC substrate motif that is part of a 3-nucleotide loop. In addition, the structural basis of APOBEC3A’s preference for YTCD motifs (Y = T, C; D = A, G, T) is explained. The nuclease-resistant phosphorothioated derivatives of these inhibitors have nanomolar potency in vitro and block APOBEC3A activity in human cells. These inhibitors may be useful probes for studying APOBEC3A activity in cellular systems and leading toward, potentially as conjuvants, next-generation, combinatorial anti-mutator and anti-cancer therapies.

Suggested Citation

  • Stefan Harjes & Harikrishnan M. Kurup & Amanda E. Rieffer & Maitsetseg Bayarjargal & Jana Filitcheva & Yongdong Su & Tracy K. Hale & Vyacheslav V. Filichev & Elena Harjes & Reuben S. Harris & Geoffrey, 2023. "Structure-guided inhibition of the cancer DNA-mutating enzyme APOBEC3A," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42174-w
    DOI: 10.1038/s41467-023-42174-w
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    References listed on IDEAS

    as
    1. Atanu Maiti & Wazo Myint & Tapan Kanai & Krista Delviks-Frankenberry & Christina Sierra Rodriguez & Vinay K. Pathak & Celia A. Schiffer & Hiroshi Matsuo, 2018. "Crystal structure of the catalytic domain of HIV-1 restriction factor APOBEC3G in complex with ssDNA," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    2. Atanu Maiti & Adam K. Hedger & Wazo Myint & Vanivilasini Balachandran & Jonathan K. Watts & Celia A. Schiffer & Hiroshi Matsuo, 2022. "Structure of the catalytically active APOBEC3G bound to a DNA oligonucleotide inhibitor reveals tetrahedral geometry of the transition state," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    3. Adam Langenbucher & Danae Bowen & Ramin Sakhtemani & Elodie Bournique & Jillian F. Wise & Lee Zou & Ashok S. Bhagwat & Rémi Buisson & Michael S. Lawrence, 2021. "An extended APOBEC3A mutation signature in cancer," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    4. Michael B. Burns & Lela Lackey & Michael A. Carpenter & Anurag Rathore & Allison M. Land & Brandon Leonard & Eric W. Refsland & Delshanee Kotandeniya & Natalia Tretyakova & Jason B. Nikas & Douglas Ye, 2013. "APOBEC3B is an enzymatic source of mutation in breast cancer," Nature, Nature, vol. 494(7437), pages 366-370, February.
    5. Ludmil B. Alexandrov & Jaegil Kim & Nicholas J. Haradhvala & Mi Ni Huang & Alvin Wei Tian Ng & Yang Wu & Arnoud Boot & Kyle R. Covington & Dmitry A. Gordenin & Erik N. Bergstrom & S. M. Ashiqul Islam , 2023. "Author Correction: The repertoire of mutational signatures in human cancer," Nature, Nature, vol. 614(7948), pages 41-41, February.
    6. Mia Petljak & Alexandra Dananberg & Kevan Chu & Erik N. Bergstrom & Josefine Striepen & Patrick Morgen & Yanyang Chen & Hina Shah & Julian E. Sale & Ludmil B. Alexandrov & Michael R. Stratton & John M, 2022. "Mechanisms of APOBEC3 mutagenesis in human cancer cells," Nature, Nature, vol. 607(7920), pages 799-807, July.
    7. Shraddha Sharma & Santosh K. Patnaik & R. Thomas Taggart & Eric D. Kannisto & Sally M. Enriquez & Paul Gollnick & Bora E. Baysal, 2015. "APOBEC3A cytidine deaminase induces RNA editing in monocytes and macrophages," Nature Communications, Nature, vol. 6(1), pages 1-15, November.
    8. Takahide Kouno & Tania V. Silvas & Brendan J. Hilbert & Shivender M. D. Shandilya & Markus F. Bohn & Brian A. Kelch & William E. Royer & Mohan Somasundaran & Nese Kurt Yilmaz & Hiroshi Matsuo & Celia , 2017. "Crystal structure of APOBEC3A bound to single-stranded DNA reveals structural basis for cytidine deamination and specificity," Nature Communications, Nature, vol. 8(1), pages 1-8, April.
    9. Michael B. Burns & Lela Lackey & Michael A. Carpenter & Anurag Rathore & Allison M. Land & Brandon Leonard & Eric W. Refsland & Delshanee Kotandeniya & Natalia Tretyakova & Jason B. Nikas & Douglas Ye, 2013. "Correction: Corrigendum: APOBEC3B is an enzymatic source of mutation in breast cancer," Nature, Nature, vol. 502(7472), pages 580-580, October.
    10. Pégah Jalili & Danae Bowen & Adam Langenbucher & Shinho Park & Kevin Aguirre & Ryan B. Corcoran & Angela G. Fleischman & Michael S. Lawrence & Lee Zou & Rémi Buisson, 2020. "Quantification of ongoing APOBEC3A activity in tumor cells by monitoring RNA editing at hotspots," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    11. In-Ja L. Byeon & Jinwoo Ahn & Mithun Mitra & Chang-Hyeock Byeon & Kamil Hercík & Jozef Hritz & Lisa M. Charlton & Judith G. Levin & Angela M. Gronenborn, 2013. "NMR structure of human restriction factor APOBEC3A reveals substrate binding and enzyme specificity," Nature Communications, Nature, vol. 4(1), pages 1-11, October.
    12. Ludmil B. Alexandrov & Jaegil Kim & Nicholas J. Haradhvala & Mi Ni Huang & Alvin Wei Tian Ng & Yang Wu & Arnoud Boot & Kyle R. Covington & Dmitry A. Gordenin & Erik N. Bergstrom & S. M. Ashiqul Islam , 2020. "The repertoire of mutational signatures in human cancer," Nature, Nature, vol. 578(7793), pages 94-101, February.
    13. Xiao Xiao & Shu-Xing Li & Hanjing Yang & Xiaojiang S. Chen, 2016. "Crystal structures of APOBEC3G N-domain alone and its complex with DNA," Nature Communications, Nature, vol. 7(1), pages 1-11, November.
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    Cited by:

    1. Ambrocio Sanchez & Pedro Ortega & Ramin Sakhtemani & Lavanya Manjunath & Sunwoo Oh & Elodie Bournique & Alexandrea Becker & Kyumin Kim & Cameron Durfee & Nuri Alpay Temiz & Xiaojiang S. Chen & Reuben , 2024. "Mesoscale DNA features impact APOBEC3A and APOBEC3B deaminase activity and shape tumor mutational landscapes," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    2. Hanjing Yang & Josue Pacheco & Kyumin Kim & Ayub Bokani & Fumiaki Ito & Diako Ebrahimi & Xiaojiang S. Chen, 2024. "Molecular mechanism for regulating APOBEC3G DNA editing function by the non-catalytic domain," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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