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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: LKB1 preserves genome integrity by stimulating BRCA1 expression.

Authors: Gupta, Romi; Liu, Alex Y; Glazer, Peter M; Wajapeyee, Narendra

Published In Nucleic Acids Res, (2015 Jan)

Abstract: Serine/threonine kinase 11 (STK11, also known as LKB1) functions as a tumor suppressor in many human cancers. However, paradoxically loss of LKB1 in mouse embryonic fibroblast results in resistance to oncogene-induced transformation. Therefore, it is unclear why loss of LKB1 leads to increased predisposition to develop a wide variety of cancers. Here, we show that LKB1 protects cells from genotoxic stress. Cells lacking LKB1 display increased sensitivity to irradiation, accumulates more DNA double-strand breaks, display defective homology-directed DNA repair (HDR) and exhibit increased mutation rate, compared with that of LKB1-expressing cells. Conversely, the ectopic expression of LKB1 in cells lacking LKB1 protects them against genotoxic stress-induced DNA damage and prevents the accumulation of mutations. We find that LKB1 post-transcriptionally stimulates HDR gene BRCA1 expression by inhibiting the cytoplasmic localization of the RNA-binding protein, HU antigen R, in an AMP kinase-dependent manner and stabilizes BRCA1 mRNA. Cells lacking BRCA1 similar to the cell lacking LKB1 display increased genomic instability and ectopic expression of BRCA1 rescues LKB1 loss-induced sensitivity to genotoxic stress. Collectively, our results demonstrate that LKB1 is a crucial regulator of genome integrity and reveal a novel mechanism for LKB1-mediated tumor suppression with direct therapeutic implications for cancer prevention.

PubMed ID: 25488815 Exiting the NIEHS site

MeSH Terms: AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases/metabolism; Animals; BRCA1 Protein/genetics*; BRCA1 Protein/metabolism; Cell Cycle; Cell Line; DNA Breaks, Double-Stranded; DNA Damage; ELAV Proteins/metabolism; Genome; Humans; Mice; Mutation; Protein Serine-Threonine Kinases/physiology*; RNA Stability; RNA, Messenger/metabolism; Recombinational DNA Repair*

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