Rbbp4 loss disrupts neural progenitor cell cycle regulation independent of Rb and leads to Tp53 acetylation and apoptosis

Schultz‐Rogers, Laura; Thayer, Michelle L; Sekhar, Kondapalli Venkata Gowri Chandra; Wierson, Wesley A.; Helmer, Jordan A; Wishman, Mark D; Wall, Kristen A; Greig, Jessica L; Forsman, Jaimie L; Puchhalapalli, Kavya; Nair, Siddharth; Weiss, Trevor; Luiken, Jon M; Blackburn, Patrick R.; Ekker, Stephen C.; Kool, Marcel; McGrail, Maura

doi:10.1002/dvdy.467

Cited by 12 publications

(7 citation statements)

References 60 publications

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“…Another transcription factor with parallel mutations that affected gene expression was HMPREF1120_05223. The top 2 co-expressed genes include chromatin packing genes H2A/H2B and H3/H4 histone acetyltransferase (HMPREF1120_07775) and RBBP4 (HMPREF1120_07289), which are also involved in DNA repair ( 43 , 44 ). Two genes that correlated with the transcription factor are involved in protein synthesis: glutamyl-tRNA synthetase (HMPREF1120_03118) and elongator complex protein 1 (HMPREF1120_03655).…”

Section: Resultsmentioning

confidence: 99%

Transcriptomic and genomic effects of gamma-radiation exposure on strains of the black yeast Exophiala dermatitidis evolved to display increased ionizing radiation resistance

Yuzon,

Schultzhaus,

Wang

2023

Microbiol Spectr

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Melanized fungi thrive in extreme environments, including those with high levels of ionizing radiation. To understand the role that melanin may play in ionizing radiation resistance, we previously performed an adaptive laboratory evolution experiment in which we used melanized and non-melanized strains of the yeast Exophiala dermatitidis to develop evolved lines that exhibit increased ionizing radiation resistance. In this study, we further characterized these evolved lines by analyzing their response to ionizing radiation at the transcriptomic and genomic levels. RNA sequencing showed that the response to gamma irradiation in both unevolved and evolved strains involved the induction of DNA repair genes. However, in the melanized lines evolved to exhibit increased ionizing radiation resistance, DNA-associated genes were constitutively expressed, compared to their expression levels in wild type. Non-melanized lines that were evolved to be resistant to ionizing radiation, on the other hand, exhibited upregulation of genes involved in redox homeostasis, even under non-irradiated conditions. Additionally, we characterized genome-wide mutations induced by a single high dose of gamma radiation in these evolved lines and observed that while melanin did not directly affect survival after gamma radiation exposure, melanized lines that evolved to exhibit higher ionizing radiation resistance experienced fewer mutations, whereas similarly evolved, non-melanized lines accumulated more mutations, similar to the parent, non-melanized strain. These results underscore the complex yet measurable role of melanin in the response to ionizing radiation in E. dermatitidis . Furthermore, this study enhances our understanding of the mechanisms underlying the recovery after ionizing radiation exposure in melanized fungi and offers insights into the potential therapeutic applications of melanin and other redox molecules for protecting against ionizing radiation-induced damage. IMPORTANCE Ionizing radiation poses a significant threat to living organisms and human health, given its destructive nature and widespread use in fields such as medicine and the potential for nuclear disasters. Melanized fungi exhibit remarkable survival capabilities, enduring doses up to 1,000-fold higher than mammals. Through adaptive laboratory evolution, we validated the protective role of constitutive upregulation of DNA repair genes in the black yeast Exophiala dermatitidis , enhancing survival after radiation exposure. Surprisingly, we found that evolved strains lacking melanin still achieved high levels of radioresistance. Our study unveiled the significance of robust activation and enhancement of redox homeostasis, as evidenced by the profound transcriptional changes and increased accumulation of mutations, in substantially improving ionizing radiation resistance in the absence of melanin. These findings underscore the delicate balance between DNA repair and redox homeostasis for an organism’s ability to endure and recover from radiation exposure.

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Section: Resultsmentioning

confidence: 99%

Transcriptomic and genomic effects of gamma-radiation exposure on strains of the black yeast Exophiala dermatitidis evolved to display increased ionizing radiation resistance

Yuzon,

Schultzhaus,

Wang

2023

Microbiol Spectr

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“…It should be noted that, according to the literature data, they seemingly act in regulating the balance between pro-apoptotic and cell survival signals. Data on these elements mainly refer to their role in carcinogenesis [57][58][59]. Nevertheless, some hypotheses can be drafted from this data: the down-regulation of HMGN4 and RBBP4, as well as the up-regulation of KDM5D tend toward pro-apoptotic signaling.…”

Section: Discussionmentioning

confidence: 99%

“…Consequently, reducing its expression may trigger an opposite effect, promoting cell cycle arrest and apoptotic signaling. Finally, it has been observed that RBBP4 loss disrupts neural progenitor cell cycle regulation and leads to Tp53 acetylation and apoptosis [59].…”

Section: Discussionmentioning

confidence: 99%

Network Analysis Performed on Transcriptomes of Parkinson’s Disease Patients Reveals Dysfunction in Protein Translation

D’Angiolini,

Lui,

Mazzon

et al. 2024

IJMS

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Parkinson’s disease (PD) is a prevalent neurodegenerative disorder characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra region of the brain. The hallmark pathological feature of PD is the accumulation of misfolded proteins, leading to the formation of intracellular aggregates known as Lewy bodies. Recent data evidenced how disruptions in protein synthesis, folding, and degradation are events commonly observed in PD and may provide information on the molecular background behind its etiopathogenesis. In the present study, we used a publicly available transcriptomic microarray dataset of peripheral blood of PD patients and healthy controls (GSE6613) to investigate the potential dysregulation of elements involved in proteostasis-related processes at the transcriptomic level. Our bioinformatics analysis revealed 375 differentially expressed genes (DEGs), of which 281 were down-regulated and 94 were up-regulated. Network analysis performed on the observed DEGs highlighted a cluster of 36 elements mainly involved in the protein synthesis processes. Different enriched ontologies were related to translation initiation and regulation, ribosome structure, and ribosome components nuclear export. Overall, this data consistently points to a generalized impairment of the translational machinery and proteostasis. Dysregulation of these mechanics has been associated with PD pathogenesis. Understanding the precise regulation of such processes may shed light on the molecular mechanisms of PD and provide potential data for early diagnosis.

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“…Studies conducted in yeast and cultured cells have shown that RBBP4 appears to function as a tumor suppressor along with RB, leading to inhibition of cell cycle progression and cell growth ( 16 , 18 ). Nevertheless, Schultz-Rogers et al ( 31 ) indicated that RBBP4 is essential for the cell cycle progression of neural progenitor cells and the initiation of G 0 , irrespective of the involvement of RB. The E2F family plays a key role in cell cycle regulation, and all RB family members interact with typical E2F proteins to form transcriptional inhibition complexes ( 32 ).…”

Section: The Biological Functions Of Rbbp4/7mentioning

confidence: 99%

Interpreting the molecular mechanisms of RBBP4/7 and their roles in human diseases (Review)

Zhan,

Yin,

et al. 2024

Int J Mol Med

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Histone chaperones serve a pivotal role in maintaining human physiological processes. They interact with histones in a stable manner, ensuring the accurate and efficient execution of DNA replication, repair and transcription. Retinoblastoma binding protein (RBBP)4 and RBBP7 represent a crucial pair of histone chaperones, which not only govern the molecular behavior of histones H3 and H4, but also participate in the functions of several protein complexes, such as polycomb repressive complex 2 and nucleosome remodeling and deacetylase, thereby regulating the cell cycle, histone modifications, DNA damage and cell fate. A strong association has been indicated between RBBP4/7 and some major human diseases, such as cancer, age-related memory loss and infectious diseases. The present review assesses the molecular mechanisms of RBBP4/7 in regulating cellular biological processes, and focuses on the variations in RBBP4/7 expression and their potential mechanisms in various human diseases, thus providing new insights for their diagnosis and treatment.

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Rbbp4 loss disrupts neural progenitor cell cycle regulation independent of Rb and leads to Tp53 acetylation and apoptosis

Cited by 12 publications

References 60 publications

Transcriptomic and genomic effects of gamma-radiation exposure on strains of the black yeast Exophiala dermatitidis evolved to display increased ionizing radiation resistance

Transcriptomic and genomic effects of gamma-radiation exposure on strains of the black yeast Exophiala dermatitidis evolved to display increased ionizing radiation resistance

Network Analysis Performed on Transcriptomes of Parkinson’s Disease Patients Reveals Dysfunction in Protein Translation

Interpreting the molecular mechanisms of RBBP4/7 and their roles in human diseases (Review)

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