Pathway choice in the alternative telomere lengthening in neoplasia is dictated by replication fork processing mediated by EXD2’s nuclease activity

Ronan Broderick, Veronica Cherdyntseva, Jadwiga Nieminuszczy, Eleni Dragona, Maria Kyriakaki, Theodora Evmorfopoulou, Sarantis Gagos () and Wojciech Niedzwiedz ()
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Ronan Broderick: The Institute of Cancer Research
Veronica Cherdyntseva: Experimental Surgery and Translational Research Biomedical Research Foundation Academy of Athens (BRFAA)
Jadwiga Nieminuszczy: The Institute of Cancer Research
Eleni Dragona: Experimental Surgery and Translational Research Biomedical Research Foundation Academy of Athens (BRFAA)
Maria Kyriakaki: Experimental Surgery and Translational Research Biomedical Research Foundation Academy of Athens (BRFAA)
Theodora Evmorfopoulou: Experimental Surgery and Translational Research Biomedical Research Foundation Academy of Athens (BRFAA)
Sarantis Gagos: Experimental Surgery and Translational Research Biomedical Research Foundation Academy of Athens (BRFAA)
Wojciech Niedzwiedz: The Institute of Cancer Research

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Telomerase-independent cancer proliferation via the alternative lengthening of telomeres (ALT) relies upon two distinct, largely uncharacterized, break-induced-replication (BIR) processes. How cancer cells initiate and regulate these terminal repair mechanisms is unknown. Here, we establish that the EXD2 nuclease is recruited to ALT telomeres to direct their maintenance. We demonstrate that EXD2 loss leads to telomere shortening, elevated telomeric sister chromatid exchanges, C-circle formation as well as BIR-mediated telomeric replication. We discover that EXD2 fork-processing activity triggers a switch between RAD52-dependent and -independent ALT-associated BIR. The latter is suppressed by EXD2 but depends specifically on the fork remodeler SMARCAL1 and the MUS81 nuclease. Thus, our findings suggest that processing of stalled replication forks orchestrates elongation pathway choice at ALT telomeres. Finally, we show that co-depletion of EXD2 with BLM, DNA2 or POLD3 confers synthetic lethality in ALT cells, identifying EXD2 as a potential druggable target for ALT-reliant cancers.

Date: 2023
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DOI: 10.1038/s41467-023-38029-z

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