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MMEJ repair of breaks at TA repeats maintains ecDNA and cancer fitness

Nature Cancer Genomics David Billing, Monica Selvaraj, Megan E. Kelley, Gabriel Matos-Rodrigues, Benton Bailey, Finnja Becker, Gang Zhen, Matthew A. Myers, Alessandra Brambati, Oluchi Ezekwenna, Ashley Nichols, Yi-Zhen Jiang, Lucia Wang, Shih-Chun Wang, Marie-Claude Mathieu, Davide Pradella, Hugo Poirier, Elias Rodriguez-Fos, Stephen J. Morris, Michal Zimmermann, Elsa Callen, Michael Zinda, Andrea Ventura, John Maciejowski, Andrew McPherson, Sohrab P. Shah, Anton George Henssen, André Nussenzweig, Agnel Sfeir 2026-09-23

TL;DR - This Nature study links extrachromosomal DNA (ecDNA) stability in cancer to microhomology-mediated end joining at fragile TA-rich sites. Targeting Polθ may destabilize ecDNA and create a therapeutic vulnerability in ecDNA-driven tumours.

TA-rich sites are prone to breaks that threaten ecDNA maintenance.
Microhomology-mediated end joining repairs these breaks and preserves cancer fitness.
FANCM suppresses break formation at these fragile sites.
Disrupting Polθ-mediated repair could sensitize ecDNA-driven tumours to treatment.

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