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VCP maintains nuclear size by regulating the DNA damage-associated MDC1–p53–autophagy axis in Drosophila

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  • Ya-Chu Chang

    (National Tsing Hua University
    National Tsing Hua University)

  • Yu-Xiang Peng

    (National Tsing Hua University)

  • Bo-Hua Yu

    (National Tsing Hua University)

  • Henry C. Chang

    (Purdue University)

  • Pei-Shin Liang

    (National Tsing Hua University)

  • Ting-Yi Huang

    (National Tsing Hua University)

  • Chao-Jie Shih

    (National Tsing Hua University)

  • Li-An Chu

    (National Tsing Hua University
    National Tsing Hua University)

  • Tzu-Kang Sang

    (National Tsing Hua University
    National Tsing Hua University)

Abstract

The maintenance of constant karyoplasmic ratios suggests that nuclear size has physiological significance. Nuclear size anomalies have been linked to malignant transformation, although the mechanism remains unclear. By expressing dominant-negative TER94 mutants in Drosophila photoreceptors, here we show disruption of VCP (valosin-containing protein, human TER94 ortholog), a ubiquitin-dependent segregase, causes progressive nuclear size increase. Loss of VCP function leads to accumulations of MDC1 (mediator of DNA damage checkpoint protein 1), connecting DNA damage or associated responses to enlarged nuclei. TER94 can interact with MDC1 and decreases MDC1 levels, suggesting that MDC1 is a VCP substrate. Our evidence indicates that MDC1 accumulation stabilizes p53A, leading to TER94K2A-associated nuclear size increase. Together with a previous report that p53A disrupts autophagic flux, we propose that the stabilization of p53A in TER94K2A-expressing cells likely hinders the removal of nuclear content, resulting in aberrant nuclear size increase.

Suggested Citation

  • Ya-Chu Chang & Yu-Xiang Peng & Bo-Hua Yu & Henry C. Chang & Pei-Shin Liang & Ting-Yi Huang & Chao-Jie Shih & Li-An Chu & Tzu-Kang Sang, 2021. "VCP maintains nuclear size by regulating the DNA damage-associated MDC1–p53–autophagy axis in Drosophila," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24556-0
    DOI: 10.1038/s41467-021-24556-0
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    References listed on IDEAS

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    1. Zhenkun Lou & Katherine Minter-Dykhouse & Xianglin Wu & Junjie Chen, 2003. "MDC1 is coupled to activated CHK2 in mammalian DNA damage response pathways," Nature, Nature, vol. 421(6926), pages 957-961, February.
    2. Yihong Ye & Hemmo H. Meyer & Tom A. Rapoport, 2001. "The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol," Nature, Nature, vol. 414(6864), pages 652-656, December.
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