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dc.contributor.authorGhule, Prachi N.
dc.contributor.authorXie, Ronglin
dc.contributor.authorColby, Jennifer L.
dc.contributor.authorJones, Stephen N.
dc.contributor.authorLian, Jane B.
dc.contributor.authorVan Wijnen, Andre J.
dc.contributor.authorStein, Janet L.
dc.contributor.authorStein, Gary S.
dc.date2022-08-11T08:08:03.000
dc.date.accessioned2022-08-23T15:40:46Z
dc.date.available2022-08-23T15:40:46Z
dc.date.issued2015-08-03
dc.date.submitted2015-10-13
dc.identifier.citationCell Cycle. 2015 Aug 3;14(15):2501-8. doi: 10.1080/15384101.2015.1049783. <a href="http://dx.doi.org/10.1080/15384101.2015.1049783">Link to article on publisher's site</a>.
dc.identifier.issn1551-4005 (Linking)
dc.identifier.doi10.1080/15384101.2015.1049783
dc.identifier.pmid26030398
dc.identifier.urihttp://hdl.handle.net/20.500.14038/26475
dc.description.abstractHistone Nuclear Factor P (HINFP) is essential for expression of histone H4 genes. Ablation of Hinfp and consequential depletion of histones alter nucleosome spacing and cause stalled replication and DNA damage that ultimately result in genomic instability. Faithful replication and packaging of newly replicated DNA are required for normal cell cycle control and proliferation. The tumor suppressor protein p53, the guardian of the genome, controls multiple cell cycle checkpoints and its loss leads to cellular transformation. Here we addressed whether the absence of p53 impacts the outcomes/consequences of Hinfp-mediated histone H4 deficiency. We examined mouse embryonic fibroblasts lacking both Hinfp and p53. Our data revealed that the reduced histone H4 expression caused by depletion of Hinfp persists when p53 is also inactivated. Loss of p53 enhanced the abnormalities in nuclear shape and size (i.e. multi-lobed irregularly shaped nuclei) caused by Hinfp depletion and also altered the sub-nuclear organization of Histone Locus Bodies (HLBs). In addition to the polyploid phenotype resulting from deletion of either p53 or Hinfp, inactivation of both p53 and Hinfp increased mitotic defects and generated chromosomal fragility and susceptibility to DNA damage. Thus, our study conclusively establishes that simultaneous loss of both Hinfp and the p53 checkpoint is detrimental to normal cell growth and may predispose to cellular transformation.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=26030398&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://dx.doi.org/10.1080/15384101.2015.1049783
dc.subjectCell Cycle
dc.subjectChromosome Fragmentation
dc.subjectHINFP
dc.subjectHistone Nuclear Factor P
dc.subjectHLBs
dc.subjectHistone Locus Bodies
dc.subjectHinfp
dc.subjectHistone Locus Bodies
dc.subjectMEFs
dc.subjectmouse embryonic fibroblasts
dc.subjectNPAT
dc.subjectNPAT
dc.subjectNuclear Protein Ataxia-Telangiectasia locus
dc.subjectcKO
dc.subjectconditional knockout
dc.subjectdKO
dc.subjectdouble knockout
dc.subjecthistone H4
dc.subjectp53
dc.subjectCell Biology
dc.subjectGenetics
dc.titlep53 checkpoint ablation exacerbates the phenotype of Hinfp dependent histone H4 deficiency
dc.typeJournal Article
dc.source.journaltitleCell cycle (Georgetown, Tex.)
dc.source.volume14
dc.source.issue15
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/cellbiology_pp/160
dc.identifier.contextkey7709827
html.description.abstract<p>Histone Nuclear Factor P (HINFP) is essential for expression of histone H4 genes. Ablation of Hinfp and consequential depletion of histones alter nucleosome spacing and cause stalled replication and DNA damage that ultimately result in genomic instability. Faithful replication and packaging of newly replicated DNA are required for normal cell cycle control and proliferation. The tumor suppressor protein p53, the guardian of the genome, controls multiple cell cycle checkpoints and its loss leads to cellular transformation. Here we addressed whether the absence of p53 impacts the outcomes/consequences of Hinfp-mediated histone H4 deficiency. We examined mouse embryonic fibroblasts lacking both Hinfp and p53. Our data revealed that the reduced histone H4 expression caused by depletion of Hinfp persists when p53 is also inactivated. Loss of p53 enhanced the abnormalities in nuclear shape and size (i.e. multi-lobed irregularly shaped nuclei) caused by Hinfp depletion and also altered the sub-nuclear organization of Histone Locus Bodies (HLBs). In addition to the polyploid phenotype resulting from deletion of either p53 or Hinfp, inactivation of both p53 and Hinfp increased mitotic defects and generated chromosomal fragility and susceptibility to DNA damage. Thus, our study conclusively establishes that simultaneous loss of both Hinfp and the p53 checkpoint is detrimental to normal cell growth and may predispose to cellular transformation.</p>
dc.identifier.submissionpathcellbiology_pp/160
dc.contributor.departmentDepartment of Cell and Developmental Biology
dc.source.pages2501-8


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