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

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ya-Chu Chang ◽  
Yu-Xiang Peng ◽  
Bo-Hua Yu ◽  
Henry C. Chang ◽  
Pei-Shin Liang ◽  
...  
Keyword(s):  
Dna Damage ◽  
Malignant Transformation ◽  
Dominant Negative ◽  
Nuclear Size ◽  
Physiological Significance ◽  
Size Increase ◽  
Dna Damage Checkpoint ◽  
Autophagic Flux ◽  
Checkpoint Protein ◽  
Nuclear Content

AbstractThe 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.

scholarly journals VCP functions to maintain nuclear size by managing DNA damage-induced MDC1–p53–autophagy axis

2020 ◽  
Author(s):  
Ya-Chu Chang ◽  
Yu-Xiang Peng ◽  
Chao-Jie Shih ◽  
Henry Chang ◽  
Tzu-Kang Sang
Keyword(s):  
Dna Damage ◽  
Dominant Negative ◽  
Nuclear Size ◽  
Size Increase ◽  
Autophagic Flux ◽  
Response Gene ◽  
Dna Damages ◽  
Aaa Atpase ◽  
Damage Response ◽  
Age Dependent

Abstract 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 (TER94K2A) mutants in Drosophila photoreceptors, we show disruption of VCP (valosin-containing protein, TER94 ortholog in human), an AAA (ATPase associated with various cellular activities) ATPase essential for ubiquitin-dependent segregation or degradation of proteins, causes an age-dependent nuclear size increase. Loss of VCP function leads to accumulations of MDC1 (mediator of DNA damage checkpoint protein 1), a key DNA damage response gene, and increased γH2AV (an indicator of DNA damage), linking excessive DNA damages and associated responses to this enlarged nuclei defect. Indeed, MDC1-overexpression, similar to TER94K2A, increases γH2AV staining and nuclear size. Moreover, TER94 negatively influences MDC1 level and could interact with MDC1, suggesting that MDC1 is a VCP substrate. MDC1 accumulation increases p53 stability, and this VCP-MDC1-p53 connection is functional, as removal of p53 function suppresses the ability of TER94K2A and MDC1 overexpression to increase nuclear size. While p53 is capable of generating multiple isoforms, our genetic evidence suggests that the p53A isoform specifically contributes to this TER94K2A-associated nuclear size increase. Combining our results with a previous report that p53A expression disrupts autophagic flux, we propose that the failure of removing MDC1 in TER94K2A-expressing cells stabilizes p53A, which blocks autophagy and likely hinders the removal of nuclear content, resulting in aberrant nuclear size increase.

scholarly journals The DNA damage checkpoint protein ATM promotes hepatocellular apoptosis and fibrosis in a mouse model of non-alcoholic fatty liver disease

Cell Cycle ◽  
2012 ◽  
Vol 11 (10) ◽  
pp. 1918-1928 ◽  
Author(s):  
Erin K. Daugherity ◽  
Gabriel Balmus ◽  
Ahmed Al Saei ◽  
Elizabeth S. Moore ◽  
Delbert Abi Abdallah ◽  
...  
Keyword(s):  
Dna Damage ◽  
Liver Disease ◽  
Mouse Model ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Dna Damage Checkpoint ◽  
Alcoholic Fatty Liver ◽  
Checkpoint Protein ◽  
Hepatocellular Apoptosis ◽  
Alcoholic Fatty Liver Disease

TORC1 regulates the DNA damage checkpoint via checkpoint protein levels

2019 ◽  
Vol 510 (4) ◽  
pp. 629-635 ◽  
Author(s):  
Ikuko Miyamoto ◽  
Ryota Ozaki ◽  
Kazuyuki Yamaguchi ◽  
Kaori Yamamoto ◽  
Atsuki Kaneko ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Checkpoint ◽  
Checkpoint Protein ◽  
Protein Levels

The DNA damage checkpoint protein RAD9A is essential for male meiosis in the mouse

Development ◽  
2013 ◽  
Vol 140 (19) ◽  
pp. e1907-e1907
Author(s):  
Ana Vasileva ◽  
Kevin M. Hopkins ◽  
Xiangyuan Wang ◽  
Melissa M. Weisbach ◽  
Richard A. Friedman ◽  
...  
Keyword(s):  
Dna Damage ◽  
Male Meiosis ◽  
Dna Damage Checkpoint ◽  
Checkpoint Protein

scholarly journals Sexual dimorphism in the meiotic requirement for PRDM9: a mammalian evolutionary safeguard

2020 ◽  
Author(s):  
Natalie R Powers ◽  
Beth L Dumont ◽  
Chihiro Emori ◽  
Raman Akinyanju Lawal ◽  
Catherine Brunton ◽  
...  
Keyword(s):  
Dna Damage ◽  
Meiotic Recombination ◽  
Genetic Background ◽  
Dna Damage Checkpoint ◽  
Human Female ◽  
Female Meiosis ◽  
Checkpoint Protein ◽  
Recombination System ◽  
Specific Regulation ◽  
Female Specific

AbstractIn many mammals, genomic sites for recombination are determined by histone methyltransferase PRMD9. Mice lacking PRDM9 are infertile, but instances of fertility or semi-fertility in the absence of PRDM9 have been reported in mice, canines and a human female. Such findings raise the question of how the loss of PRDM9 is circumvented to maintain reproductive fitness. We show that genetic background and sex-specific modifiers can obviate the requirement for PRDM9 in mice. Specifically, the meiotic DNA damage checkpoint protein CHK2 acts as a modifier allowing female-specific fertility in the absence of PRDM9. We also report that in the absence of PRDM9, a PRDM9-independent recombination system is compatible with female meiosis and fertility, suggesting sex-specific regulation of meiotic recombination, a finding with implications for speciation.One Sentence SummarySex-specific modulation of a meiotic DNA damage checkpoint limits the requirement for PRDM9 in mammalian fertility.

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