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DAXX-ATRX regulation of p53 chromatin binding and DNA damage response

Author

Listed:
  • Nitish Gulve

    (The Wistar Institute)

  • Chenhe Su

    (The Wistar Institute)

  • Zhong Deng

    (The Wistar Institute)

  • Samantha S. Soldan

    (The Wistar Institute)

  • Olga Vladimirova

    (The Wistar Institute)

  • Jayamanna Wickramasinghe

    (The Wistar Institute)

  • Hongwu Zheng

    (Cornell University)

  • Andrew V. Kossenkov

    (The Wistar Institute)

  • Paul. M. Lieberman

    (The Wistar Institute)

Abstract

DAXX and ATRX are tumor suppressor proteins that form a histone H3.3 chaperone complex and are frequently mutated in cancers with the alternative lengthening of telomeres (ALT). Here, we show that DAXX and ATRX knock-out (KO) U87-T cells that have acquired ALT-like features have defects in p53 chromatin binding and DNA damage response. RNA-seq analysis revealed that p53 pathway is among the most perturbed. ChIP-seq and ATAC-seq revealed a genome-wide reduction in p53 DNA-binding and corresponding loss of chromatin accessibility at many p53 response elements across the genome. Both DAXX and ATRX null cells showed a depletion of histone H3.3 and accumulation of γH2AX at many p53 sites, including subtelomeres. These findings indicate that loss of DAXX or ATRX can compromise p53 chromatin binding and p53 DNA damage response in ALT-like cells, providing a link between histone composition, chromatin accessibility and tumor suppressor function of p53.

Suggested Citation

  • Nitish Gulve & Chenhe Su & Zhong Deng & Samantha S. Soldan & Olga Vladimirova & Jayamanna Wickramasinghe & Hongwu Zheng & Andrew V. Kossenkov & Paul. M. Lieberman, 2022. "DAXX-ATRX regulation of p53 chromatin binding and DNA damage response," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32680-8
    DOI: 10.1038/s41467-022-32680-8
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    1. Julia Truch & Damien J. Downes & Caroline Scott & E. Ravza Gür & Jelena M. Telenius & Emmanouela Repapi & Ron Schwessinger & Matthew Gosden & Jill M. Brown & Stephen Taylor & Pak Leng Cheong & Jim R. , 2022. "The chromatin remodeller ATRX facilitates diverse nuclear processes, in a stochastic manner, in both heterochromatin and euchromatin," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Liangqian Huang & Trisha Agrawal & Guixin Zhu & Sixiang Yu & Liming Tao & JiaBei Lin & Ronen Marmorstein & James Shorter & Xiaolu Yang, 2021. "DAXX represents a new type of protein-folding enabler," Nature, Nature, vol. 597(7874), pages 132-137, September.
    3. Qingqing Yan & Phillip Wulfridge & John Doherty & Jose L. Fernandez-Luna & Pedro J. Real & Hsin-Yao Tang & Kavitha Sarma, 2022. "Proximity labeling identifies a repertoire of site-specific R-loop modulators," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    4. Yu-Ching Teng & Aishwarya Sundaresan & Ryan O’Hara & Vincent U. Gant & Minhua Li & Sara Martire & Jane N. Warshaw & Amrita Basu & Laura A. Banaszynski, 2021. "ATRX promotes heterochromatin formation to protect cells from G-quadruplex DNA-mediated stress," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    5. David Clynes & Clare Jelinska & Barbara Xella & Helena Ayyub & Caroline Scott & Matthew Mitson & Stephen Taylor & Douglas R. Higgs & Richard J. Gibbons, 2015. "Suppression of the alternative lengthening of telomere pathway by the chromatin remodelling factor ATRX," Nature Communications, Nature, vol. 6(1), pages 1-11, November.
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    Cited by:

    1. Iqbal Mahmud & Guimei Tian & Jia Wang & Tarun E. Hutchinson & Brandon J. Kim & Nikee Awasthee & Seth Hale & Chengcheng Meng & Allison Moore & Liming Zhao & Jessica E. Lewis & Aaron Waddell & Shangtao , 2023. "DAXX drives de novo lipogenesis and contributes to tumorigenesis," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

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