Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0344329 (collapse)
 28,634 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Saccharomyces cerevisiae NuA4 histone acetyltransferase complex catalyzes the acetylation of histone H4 and the histone variant Htz1 to regulate key cellular events, including transcription, DNA repair, and faithful chromosome segregation. To further investigate the cellular processes impacted by NuA4, we exploited the nonessential subunits of the complex to build an extensive NuA4 genetic-interaction network map. The map reveals that NuA4 is a genetic hub whose function buffers a diverse range of cellular processes, many not previously linked to the complex, including Golgi complex-to-vacuole vesicle-mediated transport. Further, we probe the role that nonessential subunits play in NuA4 complex integrity. We find that most nonessential subunits have little impact on NuA4 complex integrity and display between 12 and 42 genetic interactions. In contrast, the deletion of EAF1 causes the collapse of the NuA4 complex and displays 148 genetic interactions. Our study indicates that Eaf1 plays a crucial function in NuA4 complex integrity. Further, we determine that Eaf5 and Eaf7 form a subcomplex, which reflects their similar genetic interaction profiles and phenotypes. Our integrative study demonstrates that genetic interaction maps are valuable in dissecting complex structure and provides insight into why the human NuA4 complex, Tip60, has been associated with a diverse range of pathologies.
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PMID:Functional dissection of the NuA4 histone acetyltransferase reveals its role as a genetic hub and that Eaf1 is essential for complex integrity. 1821 56

During DNA replication, the advance of replication forks is tightly connected with chromatin assembly, a process that can be impaired by the partial depletion of histone H4 leading to recombinogenic DNA damage. Here, we show that the partial depletion of H4 is rapidly followed by the collapse of unperturbed and stalled replication forks, even though the S-phase checkpoints remain functional. This collapse is characterized by a reduction in the amount of replication intermediates, but an increase in single Ys relative to bubbles, defects in the integrity of the replisome and an accumulation of DNA double-strand breaks. This collapse is also associated with an accumulation of Rad52-dependent X-shaped molecules. Consistently, a Rad52-dependent--although Rad51-independent--mechanism is able to rescue these broken replication forks. Our findings reveal that correct nucleosome deposition is required for replication fork stability, and provide molecular evidence for homologous recombination as an efficient mechanism of replication fork restart.
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PMID:Chromatin assembly controls replication fork stability. 1946 89

Successful DNA replication and packaging of newly synthesized DNA into chromatin are essential to maintain genome integrity. Defects in the DNA template challenge genetic and epigenetic inheritance. Unfortunately, tracking DNA damage responses (DDRs), histone deposition, and chromatin maturation at replication forks is difficult in mammalian cells. Here we describe a technology called iPOND (isolation of proteins on nascent DNA) to analyze proteins at active and damaged replication forks at high resolution. Using this methodology, we define the timing of histone deposition and chromatin maturation. Class 1 histone deacetylases are enriched at replisomes and remove predeposition marks on histone H4. Chromatin maturation continues even when decoupled from replisome movement. Furthermore, fork stalling causes changes in the recruitment and phosphorylation of proteins at the damaged fork. Checkpoint kinases catalyze H2AX phosphorylation, which spreads from the stalled fork to include a large chromatin domain even prior to fork collapse and double-strand break formation. Finally, we demonstrate a switch in the DDR at persistently stalled forks that includes MRE11-dependent RAD51 assembly. These data reveal a dynamic recruitment of proteins and post-translational modifications at damaged forks and surrounding chromatin. Furthermore, our studies establish iPOND as a useful methodology to study DNA replication and chromatin maturation.
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PMID:Analysis of protein dynamics at active, stalled, and collapsed replication forks. 2168 66

Collapsin response mediator proteins (CRMPs) are ubiquitously expressed in neurons from worms to humans. A cardinal feature of CRMPs is to mediate growth cone collapse in response to Semaphorin-3A signaling through interactions with cytoskeletal proteins. These are critical regulatory roles that CRMPs play during neuritogenesis and neural network formation. Through post-translational modifications, such as phosphorylation, O-GlcNAcylation, SUMOylation, and proteolytic cleavage, CRMPs participate in synaptic plasticity by modulating NMDA receptors, L- and N-type voltage-gated calcium channels (VGCCs), thus affecting neurotransmitter release. CRMPs also possess histone deacetylase (HDAC) activity, which deacetylates histone H4 during neuronal death. Calcium-dependent proteolytic cleavage of CRMPs results in the truncation of CRMPs, producing a large 54 kD fragment (p54). Translocation of the p54 fragment into the nucleus leads to deacetylation of nuclear histone H4 and de-repression of transcription factor E2F1 expression. Increased expression of E2F1 elevates the expression of genes in cell cycle and death. These new and exciting studies lead to the realization that CRMPs are multifunctional proteins with both regulatory and enzymatic functions. Increasing numbers of studies associate these functions of CRMPs with the development of mental and neurological disorders, such as schizophrenia, Alzheimer's diseases, brain trauma, and stroke. This review focuses on new evidence showing the regulatory and enzymatic functions of CRMPs and highlights recent understandings of CRMPs' roles in neurological diseases.
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PMID:The regulatory and enzymatic functions of CRMPs in neuritogenesis, synaptic plasticity, and gene transcription. 3265 66