Nuclear envelope protein lamin B receptor protects the genome from chromosomal instability and tumorigenesis

Abstract Lamin B Receptor (LBR) is an inner nuclear membrane protein that assembles the nuclear envelope post mitosis. Here we show that LBR depletion induces mitotic defects accompanied by recurrent chromosomal losses. In addition, LBR knockdown results in nuclear aberrations such as nuclear blebs...

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Bibliographic Details
Published in:Human molecular genetics 2023-02, Vol.32 (5), p.745-763
Main Authors: Patil, Shalaka, Deshpande, Shruti, Sengupta, Kundan
Format: Article
Language:English
Subjects:
Animals
Carcinogenesis
Chromosomal Instability
Humans
Lamin B Receptor
Lamin Type B - metabolism
Membrane Proteins - metabolism
Mice
Nuclear Envelope - metabolism
Receptors, Cytoplasmic and Nuclear
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Summary:Abstract Lamin B Receptor (LBR) is an inner nuclear membrane protein that assembles the nuclear envelope post mitosis. Here we show that LBR depletion induces mitotic defects accompanied by recurrent chromosomal losses. In addition, LBR knockdown results in nuclear aberrations such as nuclear blebs and micronuclei, with chromosomes showing higher frequency of losses, being enriched within the micronucleus. Furthermore, doxycycline-induced conditional depletion of LBR significantly increased tumor volumes that form within the subcutaneous xenografts of mice. Of note, the tumor-derived primary cells recapitulated chromosomal losses and gains, revealing a novel role for LBR as a tumor suppressor. Co-immunoprecipitation of LBR uncovered an association of LBR with telomere-associated factors. Interestingly, qPCR array-based gene expression profiling showed a significant upregulation of telomere repeat-binding factor 1 (TRF1) upon LBR depletion. Remarkably, TRF1 knockdown in the background of LBR depletion maintains chromosomal stability, unraveling a novel mechanism involving LBR and TRF in the maintenance of chromosomal stability in colorectal cancer cells. Graphical Abstract Graphical Abstract
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/ddac235