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Break-induced telomere synthesis underlies alternative telomere maintenance

Author

Listed:
  • Robert L. Dilley

    (Abramson Family Cancer Research Institute, Basser Research Center for BRCA, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard)

  • Priyanka Verma

    (Abramson Family Cancer Research Institute, Basser Research Center for BRCA, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard)

  • Nam Woo Cho

    (Abramson Family Cancer Research Institute, Basser Research Center for BRCA, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard)

  • Harrison D. Winters

    (Abramson Family Cancer Research Institute, Basser Research Center for BRCA, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard)

  • Anne R. Wondisford

    (Abramson Family Cancer Research Institute, Basser Research Center for BRCA, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard)

  • Roger A. Greenberg

    (Abramson Family Cancer Research Institute, Basser Research Center for BRCA, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard
    Abramson Family Cancer Research Institute, Basser Research Center for BRCA, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard)

Abstract

Homology-directed DNA repair is essential for genome maintenance through templated DNA synthesis. Alternative lengthening of telomeres (ALT) necessitates homology-directed DNA repair to maintain telomeres in about 10–15% of human cancers. How DNA damage induces assembly and execution of a DNA replication complex (break-induced replisome) at telomeres or elsewhere in the mammalian genome is poorly understood. Here we define break-induced telomere synthesis and demonstrate that it utilizes a specialized replisome, which underlies ALT telomere maintenance. DNA double-strand breaks enact nascent telomere synthesis by long-tract unidirectional replication. Proliferating cell nuclear antigen (PCNA) loading by replication factor C (RFC) acts as the initial sensor of telomere damage to establish predominance of DNA polymerase δ (Pol δ) through its POLD3 subunit. Break-induced telomere synthesis requires the RFC–PCNA–Pol δ axis, but is independent of other canonical replisome components, ATM and ATR, or the homologous recombination protein Rad51. Thus, the inception of telomere damage recognition by the break-induced replisome orchestrates homology-directed telomere maintenance.

Suggested Citation

  • Robert L. Dilley & Priyanka Verma & Nam Woo Cho & Harrison D. Winters & Anne R. Wondisford & Roger A. Greenberg, 2016. "Break-induced telomere synthesis underlies alternative telomere maintenance," Nature, Nature, vol. 539(7627), pages 54-58, November.
    • Handle: RePEc:nat:nature:v:539:y:2016:i:7627:d:10.1038_nature20099
    DOI: 10.1038/nature20099
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    Cited by:

    1. Ronan Broderick & Veronica Cherdyntseva & Jadwiga Nieminuszczy & Eleni Dragona & Maria Kyriakaki & Theodora Evmorfopoulou & Sarantis Gagos & Wojciech Niedzwiedz, 2023. "Pathway choice in the alternative telomere lengthening in neoplasia is dictated by replication fork processing mediated by EXD2’s nuclease activity," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Courtney A Lovejoy & Kaori Takai & Michael S Huh & David J Picketts & Titia de Lange, 2020. "ATRX affects the repair of telomeric DSBs by promoting cohesion and a DAXX-dependent activity," PLOS Biology, Public Library of Science, vol. 18(1), pages 1-28, January.
    3. 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-Yo, 2022. "XPF activates break-induced telomere synthesis," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    4. Valentina Buemi & Odessa Schillaci & Mariangela Santorsola & Deborah Bonazza & Pamela Veneziano Broccia & Annie Zappone & Cristina Bottin & Giulia Dell’Omo & Sylvie Kengne & Stefano Cacchione & Grazia, 2022. "TGS1 mediates 2,2,7-trimethyl guanosine capping of the human telomerase RNA to direct telomerase dependent telomere maintenance," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    5. Frances Karla Kusuma & Aishvaryaa Prabhu & Galen Tieo & Syed Moiz Ahmed & Pushkar Dakle & Wai Khang Yong & Elina Pathak & Vikas Madan & Yan Yi Jiang & Wai Leong Tam & Dennis Kappei & Peter Dröge & H. , 2023. "Signalling inhibition by ponatinib disrupts productive alternative lengthening of telomeres (ALT)," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    6. Frederick Richards & Marta J. Llorca-Cardenosa & Jamie Langton & Sara C. Buch-Larsen & Noor F. Shamkhi & Abhishek Bharadwaj Sharma & Michael L. Nielsen & Nicholas D. Lakin, 2023. "Regulation of Rad52-dependent replication fork recovery through serine ADP-ribosylation of PolD3," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    7. Ilaria Rosso & Corey Jones-Weinert & Francesca Rossiello & Matteo Cabrini & Silvia Brambillasca & Leonel Munoz-Sagredo & Zeno Lavagnino & Emanuele Martini & Enzo Tedone & Massimiliano Garre’ & Julio A, 2023. "Alternative lengthening of telomeres (ALT) cells viability is dependent on C-rich telomeric RNAs," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    8. S. Cohen & A. Guenolé & I. Lazar & A. Marnef & T. Clouaire & D. V. Vernekar & N. Puget & V. Rocher & C. Arnould & M. Aguirrebengoa & M. Genais & N. Firmin & R. A. Shamanna & R. Mourad & V. A. Bohr & V, 2022. "A POLD3/BLM dependent pathway handles DSBs in transcribed chromatin upon excessive RNA:DNA hybrid accumulation," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    9. Daniela Muoio & Natalie Laspata & Rachel L. Dannenberg & Caroline Curry & Simone Darkoa-Larbi & Mark Hedglin & Shikhar Uttam & Elise Fouquerel, 2024. "PARP2 promotes Break Induced Replication-mediated telomere fragility in response to replication stress," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    10. Fei Li & Yizhe Wang & Inah Hwang & Ja-Young Jang & Libo Xu & Zhong Deng & Eun Young Yu & Yiming Cai & Caizhi Wu & Zhenbo Han & Yu-Han Huang & Xiangao Huang & Ling Zhang & Jun Yao & Neal F. Lue & Paul , 2023. "Histone demethylase KDM2A is a selective vulnerability of cancers relying on alternative telomere maintenance," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    11. Dadong Dai & Chuanshuai Xie & Yayi Zhou & Dexin Bo & Shurong Zhang & Shengqiang Mao & Yucheng Liao & Simeng Cui & Zhaolu Zhu & Xueyu Wang & Fanling Li & Donghai Peng & Jinshui Zheng & Ming Sun, 2023. "Unzipped chromosome-level genomes reveal allopolyploid nematode origin pattern as unreduced gamete hybridization," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    12. Timothy K. Turkalo & Antonio Maffia & Johannes J. Schabort & Samuel G. Regalado & Mital Bhakta & Marco Blanchette & Diana C. J. Spierings & Peter M. Lansdorp & Dirk Hockemeyer, 2023. "A non-genetic switch triggers alternative telomere lengthening and cellular immortalization in ATRX deficient cells," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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