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

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

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: peter.ly@utsouthwestern.edu.
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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