XPF activates break-induced telomere synthesis

Chia-Yu Guh, Hong-Jhih Shen, Liv WeiChien Chen, Pei-Chen Chiu, I-Hsin Liao, Chen-Chia Lo, Yunfei Chen, Yu-Hung Hsieh, Ting-Chia Chang, Chien-Ping Yen, Yi-Yun Chen, Tom Wei-Wu Chen, Liuh-Yow Chen, Ching-Shyi Wu, Jean-Marc Egly and Hsueh-Ping Catherine Chu ()
Additional contact information
Chia-Yu Guh: National Taiwan University
Hong-Jhih Shen: National Taiwan University
Liv WeiChien Chen: National Taiwan University
Pei-Chen Chiu: National Taiwan University
I-Hsin Liao: National Taiwan University
Chen-Chia Lo: National Taiwan University
Yunfei Chen: National Taiwan University
Yu-Hung Hsieh: National Taiwan University
Ting-Chia Chang: National Taiwan University
Chien-Ping Yen: National Taiwan University
Yi-Yun Chen: Academia Sinica
Tom Wei-Wu Chen: National Taiwan University College of Medicine
Liuh-Yow Chen: Academia Sinica
Ching-Shyi Wu: National Taiwan University
Jean-Marc Egly: CNRS/INSERM/University of Strasbourg
Hsueh-Ping Catherine Chu: National Taiwan University

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: Abstract Alternative Lengthening of Telomeres (ALT) utilizes a recombination mechanism and break-induced DNA synthesis to maintain telomere length without telomerase, but it is unclear how cells initiate ALT. TERRA, telomeric repeat-containing RNA, forms RNA:DNA hybrids (R-loops) at ALT telomeres. We show that depleting TERRA using an RNA-targeting Cas9 system reduces ALT-associated PML bodies, telomere clustering, and telomere lengthening. TERRA interactome reveals that TERRA interacts with an extensive subset of DNA repair proteins in ALT cells. One of TERRA interacting proteins, the endonuclease XPF, is highly enriched at ALT telomeres and recruited by telomeric R-loops to induce DNA damage response (DDR) independent of CSB and SLX4, and thus triggers break-induced telomere synthesis and lengthening. The attraction of BRCA1 and RAD51 at telomeres requires XPF in FANCM-deficient cells that accumulate telomeric R-loops. Our results suggest that telomeric R-loops activate DDR via XPF to promote homologous recombination and telomere replication to drive ALT.

Date: 2022
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DOI: 10.1038/s41467-022-33428-0

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