Please use this identifier to cite or link to this item: http://dr.iiserpune.ac.in:8080/xmlui/handle/123456789/7400
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dc.contributor.advisorSENGUPTA, KUNDANen_US
dc.contributor.authorPATIL, SHALAKAen_US
dc.date.accessioned2022-10-20T09:13:48Z-
dc.date.available2022-10-20T09:13:48Z-
dc.date.issued2022-05en_US
dc.identifier.citation267en_US
dc.identifier.urihttp://dr.iiserpune.ac.in:8080/xmlui/handle/123456789/7400-
dc.description.abstractLamin B Receptor (LBR) is an integral protein of the inner nuclear membrane required for nuclear envelope reassembly post-mitosis. LBR and lamins are associated with heterochromatin at the nuclear envelope thereby modulating gene expression. Here we investigated the role of LBR in the regulation of chromosomal stability. Remarkably, LBR knockdown induced chromosomal instability (CIN) in colorectal cancer cells. LBR loss showed recurrent patterns of chromosomal losses and translocations, in a chromosome-specific manner. LBR knockdown deregulates mitotic fidelity by altering levels of spindle assembly checkpoint proteins - Bub1 and Mad2. In addition, LBR loss shows nuclear aberrations such as nuclear blebs and micronuclei. Strikingly, chromosomes showing a higher frequency of losses were enriched within the micronucleus. LBR depletion also showed translocations between proximal Nucleolar Organizer Region (NOR)-bearing chromosomes, with increased intermingling frequency, facilitated by a relatively open chromatin configuration. We next ectopically overexpressed full-length LBR to address if this rescues CIN. Interestingly, LBR consistently degraded, revealing a stringent control over LBR levels in diploid cell lines. In contrast, overexpression of the full-length but not mutant LBR (LBRΔ1-89), in aneuploid cell lines, increased chromosomal gains, implicating the Tudor and RS domains in the maintenance of chromosomal stability. Consistent with a significant increase in CIN, LBR loss increased tumorigenesis in xenografts that developed in athymic nude mice. Gene expression profiling showed an upregulation of Telomere Repeat-Binding factor 1 (TRF1), the knockdown of which restored chromosomal stability. Mass-spectrometry unraveled a novel sub-interactome of LBR involving the nucleolar protein - Fibrillarin (FBL), the centrosomal γ-Tubulin, and Telomeric protein - TRF2 (interactor of TRF1). Collectively, a novel LBR-TRF axis protects the genome from chromosomal losses that maintain chromosomal stability in colorectal cancer cells.en_US
dc.language.isoenen_US
dc.subjectChromosomal Instabilityen_US
dc.subjectNuclear Envelopeen_US
dc.subjectTumorigenesisen_US
dc.subjectGenome organizationen_US
dc.subjectHeterochromatinen_US
dc.titleRole of Lamin B Receptor (LBR) in nuclear organization and chromosomal stabilityen_US
dc.typeThesisen_US
dc.description.embargoOne Yearen_US
dc.type.degreePh.Den_US
dc.contributor.departmentDept. of Biologyen_US
dc.contributor.registration20153390en_US
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