The Fanconi anemia pathway induces chromothripsis and ecDNA-driven cancer drug resistance

  • Cell. 2024 Aug 20:S0092-8674(24)00892-4. doi: 10.1016/j.cell.2024.08.001.
Justin L Engel  1 ,  Xiao Zhang  2 ,  Mingming Wu  2 ,  Yan Wang  3 ,  Jose Espejo Valle-Inclán  4 ,  Qing Hu  1 ,  Kidist S Woldehawariat  1 ,  Mathijs A Sanders  5 ,  Agata Smogorzewska  6 ,  Jin Chen  7 ,  Isidro Cortés-Ciriano  4 ,  Roger S Lo  8 ,  Peter Ly  9
Affiliations
  • 1. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 2. Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 3. Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 4. European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, UK.
  • 5. Cancer, Ageing and Somatic Mutation Programme, Wellcome Sanger Institute, Hinxton CB10 1SD, UK; Department of Hematology, Erasmus MC Cancer Institute, Rotterdam 3015 GD, the Netherlands.
  • 6. Laboratory of Genome Maintenance, Rockefeller University, New York, NY 10065, USA.
  • 7. Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 8. Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 9. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: [email protected].
PMID: 39181133 DOI: 10.1016/j.cell.2024.08.001
Abstract

Chromothripsis describes the catastrophic shattering of mis-segregated chromosomes trapped within micronuclei. Although micronuclei accumulate DNA double-strand breaks and replication defects throughout interphase, how chromosomes undergo shattering remains unresolved. Using CRISPR-Cas9 screens, we identify a non-canonical role of the Fanconi anemia (FA) pathway as a driver of chromothripsis. Inactivation of the FA pathway suppresses chromosome shattering during Mitosis without impacting interphase-associated defects within micronuclei. Mono-ubiquitination of FANCI-FANCD2 by the FA core complex promotes its mitotic engagement with under-replicated micronuclear chromosomes. The structure-selective SLX4-XPF-ERCC1 Endonuclease subsequently induces large-scale nucleolytic cleavage of persistent DNA replication intermediates, which stimulates POLD3-dependent mitotic DNA synthesis to prime shattered fragments for reassembly in the ensuing cell cycle. Notably, FA-pathway-induced chromothripsis generates complex genomic rearrangements and extrachromosomal DNA that confer acquired resistance to anti-cancer therapies. Our findings demonstrate how pathological activation of a central DNA repair mechanism paradoxically triggers Cancer genome evolution through chromothripsis.

Keywords
DNA repair; DNA replication; Fanconi anemia; chromothripsis; ecDNA; fragile sites; genome rearrangements; genomic instability; micronuclei; mitosis.
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