Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P16104 (H2AX)
 3,930 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human Embryonic Stem Cells (hESCs) have a great therapeutic potential in regenerative medicine, but the precise molecular mechanisms by which hESCs maintain or regulate their characteristics remain largely unknown. Since protein-protein interaction is vitally important in regulating hESCs, we utilized a network-based bioinformatics analysis in order to learn what and how specific proteins interact with each other. By combining protein-protein interaction data and a collection of genes over-expressed in hESCs, we constructed a protein interaction network using a breadth-first search algorithm. This scale-free network which is significantly larger than networks generated by random samplings, illustrates how these hESC-enriched proteins might interact with each other in hESCs. Of the top 5% highly connected nodes (corresponding to 21 proteins including MYC, H2AFX, RUVBL1, DDX18, CDC2, HDAC2 and HIST1H4C) presumably critical for determining the fate of hESCs, nearly half are known to be regulated by NANOG/SOX2/MYC. This underscores importance of these transcription factors in hESCs. In addition, in silico cis-element analysis suggests that NF-Y may be an important transcription factor regulating many of these hub proteins (high connected nodes) in hESCs. To further abstract the functional significance, directly connected proteins were matched to and grouped by gene ontology (GO) terms in molecular function category. Sixty- six interacting GO-GO terms paired through protein interactions were found over-represented in hESCs. This functional enrichment may be essential for understanding molecular characteristics in hESCs. Collectively, we analyzed hESC-enriched genes based on protein-protein interaction data, from which an hESC-enriched protein interaction network was constructed and a network of molecular functional terms was also identified. The results of this analysis, on the systems level, may shed new light to further our understanding of hESCs.
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PMID:Enriching protein-protein and functional interaction networks in human embryonic stem cells. 1942 9

Chromatin regulators control transcription and replication, however if and how they might influence the coordination of these processes still is largely unknown. RUVBL1 and the related ATPase RUVBL2 participate in multiple nuclear processes and are implicated in cancer. Here, we report that both the excess and the deficit of the chromatin regulator RUVBL1 impede DNA replication as a consequence of altered transcription. Surprisingly, cells that either overexpressed or were silenced for RUVBL1 had slower replication fork rates and accumulated phosphorylated H2AX, dependent on active transcription. However, the mechanisms of transcription-dependent replication stress were different when RUVBL1 was overexpressed and when depleted. RUVBL1 overexpression led to increased c-Myc-dependent pause release of RNAPII, as evidenced by higher overall transcription, much stronger Ser2 phosphorylation of Rpb1- C-terminal domain, and enhanced colocalization of Rpb1 and c-Myc. RUVBL1 deficiency resulted in increased ubiquitination of Rpb1 and reduced mobility of an RNAP subunit, suggesting accumulation of stalled RNAPIIs on chromatin. Overall, our data show that by modulating the state of RNAPII complexes, RUVBL1 deregulation induces replication-transcription interference and compromises genome integrity during S-phase.
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PMID:Deregulated levels of RUVBL1 induce transcription-dependent replication stress. 3284 7