VCP maintains nuclear size by regulating the DNA damage-associated MDC1\u2013p53\u2013autophagy axis in Drosophila

Ya-Chu Chang,Tzu-Kang Sang,Henry C Chang,Bo-Hua Yu,Yu-Xiang Peng,Chao-Jie Shih,Pei-Shin Liang,Ting-Yi Huang,Li-An Chu

doi:10.1038/s41467-021-24556-0

Ya-Chu Chang, Tzu-Kang Sang + Show 7 more

Open Access

https://doi.org/10.1038/s41467-021-24556-0

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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.

Highlights

It has long been appreciated that cells keep a relatively constant karyoplasmic ratio, i.e., the proportion of nuclear volume and cytoplasmic volume[1], implying maintaining such a physiological consistency has important roles
Using both cellspecific expression of dominant-negative TER94 mutants and FLP-induced TER94k15502 mutant clones, we show that removal of TER94 function in postmitotic cells leads to an aberrant nuclear expansion
This nuclear size increase is not restricted to photoreceptors, as the expression of TER94K2A in other cell types generates a similar phenotype, suggesting that the role of TER94 in nuclear size regulation is fundamental to most cells

Summary

Introduction

It has long been appreciated that cells keep a relatively constant karyoplasmic ratio, i.e., the proportion of nuclear volume and cytoplasmic volume[1], implying maintaining such a physiological consistency has important roles. Studies from multiple systems have revealed that nuclear size is proportionally scaled to the cytoplasmic volume[1,4,5,6,7,8,9]. We investigate the molecular mechanisms linking nuclear size control and DNA damage using Drosophila TER94, the fly homolog of VCP, which is known to function in both DNA damage response (DDR) and nuclear envelope reassembly after mitosis (see below). The nuclear envelope and Golgi reassembly require VCP22,23. In the nucleus, this ubiquitindependent protein segregase/unfoldase has been reported to remove or degrade several chromatin-associated proteins involved in DDR24. Whether Drosophila TER94 has a nuclear function is not clear

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