Sustainable Development Goals
Abstract/Objectives
Anomalies in nuclear morphology have been linked to aging-related diseases and malignant transformation, although the mechanism responsible for this connection remains unclear. By expressing dominant-negative TER94 mutants, we show disruption of TER94, the fly homolog of human VCP ATPase essential for ubiquitin-dependent segregation or degradation of proteins, in Drosophila photoreceptors cause an age-dependent nuclear size increase. Loss of TER94 function leads to accumulations of Mu2 (human homolog of MDC1, mediator of DNA damage checkpoint protein 1), an essential DNA damage response gene, linking excessive DNA damages and associated responses to these enlarged nuclei defect. We present evidence that accumulated MDC1/Mu2, in a p53-dependent manner, impairs autophagy. This study may unravel the molecular mechanisms that maintain the nuclear structure and genome homeostasis in aging and several disease conditions, such as cancer, progeria, and neurodegeneration.
Results/Contributions

A condensed nucleus usually means that the cell is undergoing apoptosis. However, what happened to the cells with enlarged nuclei has been rarely explored. Abnormally enlarged nuclei have been used as a pathological marker to determine several malignant tumors. It is, therefore, crucial to understand the regulatory processes that influence the nuclear size and the physiological significance it represents. By studying the valosin-containing protein (VCP) gene - the mutation of which can lead to amyotrophic lateral sclerosis (ALS) - we found its loss of function causes abnormally enlarged nuclei. Genetic and biochemical experiments confirmed that the interaction between DNA damage repair and autophagy was the primary cause of nuclear expansion. Genome integrity is the cornerstone of health and anti-aging, and autophagy has recently been linked to aging and metabolic diseases. The findings of this study elucidate those changes in the size and shape of the nucleus can serve as a new clinical diagnostic basis.

Keywords
NucleusTER94 ATPaseMDC1p53 tumor suppressorDNA damage repairAutophagyGenome homeostasisDisease
References
Contact Information
桑自剛
tksang@life.nthu.edu.tw