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)

The polyglutamine diseases are characterized by expansion of triplet CAG repeats that encode polyglutamine tracts in otherwise unrelated proteins. One plausible explanation for the neurodegeneration of these disorders proposes that inclusions of such proteins sequester other significant nuclear proteins in inactive form. The present study shows that PML protein is sequestered by inclusions of the pathogenic mutant form of the polyglutamine protein ataxin-1 and that this sequestration removes from the nucleus the free 0.2-1 microm diameter PML nuclear domains (PML-NDs), together with at least one of their many cargo proteins (Sp100). The present study demonstrates that this sequestration can be effected equally by another nuclear protein, RED, which lacks a polyglutamine tract, but expresses a polar zipper repeat. The sequestered PML-NDs no longer respond to stress signals (heat shock or ionizing radiation) to which they are normally sensitive. In both cases, there is independent evidence that the cells initiate other responses to their injury (nuclear translocation of heat shock protein or generation of gamma-H2AX-rich nuclear foci, respectively). The data thus provide strong evidence that multiple species of nuclear inclusion functionally sequester PML-NDs. This mechanism is likely to distort cellular responses to injury of many different types.
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PMID:Stress responses of PML nuclear domains are ablated by ataxin-1 and other nucleoprotein inclusions. 1525 89

Telomerase-negative tumor cells use an alternative lengthening of telomeres (ALT) pathway that involves DNA recombination and repair to maintain their proliferative potential. The cytological hallmark of this process is the accumulation of promyelocytic leukemia (PML) nuclear protein at telomeric DNA to form ALT-associated PML bodies (APBs). Here, the de novo formation of a telomeric PML nuclear subcompartment was investigated by recruiting APB protein components. We show that functionally distinct proteins were able to initiate the formation of bona fide APBs with high efficiency in a self-organizing and self-propagating manner. These included: (1) PML and Sp100 as the constituting components of PML nuclear bodies, (2) telomere repeat binding factors 1 and 2 (TRF1 and TRF2, respectively), (3) the DNA repair protein NBS1 and (4) the SUMO E3 ligase MMS21, as well as the isolated SUMO1 domain, through an interacting domain of another protein factor. By contrast, the repair factors Rad9, Rad17 and Rad51 were less efficient in APB nucleation but were recruited to preassembled APBs. The artificially created APBs induced telomeric extension through a DNA repair mechanism, as inferred from their colocalization with sites of non-replicative DNA synthesis and histone H2A.X phosphorylation, and an increase of the telomere repeat length. These activities were absent after recruitment of the APB factors to a pericentric locus and establish APBs as functional intermediates of the ALT pathway.
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PMID:De novo assembly of a PML nuclear subcompartment occurs through multiple pathways and induces telomere elongation. 2204 32