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Nucleic Acids Res. 2015 Jan;43(1):259-71. doi: 10.1093/nar/gku1294. Epub 2014 Dec 8.

LKB1 preserves genome integrity by stimulating BRCA1 expression.

Author information

1
Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA.
2
Department of Therapeutic Radiology and Genetics, Yale University School of Medicine, New Haven, CT 06510, USA.
3
Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA narendra.wajapeyee@yale.edu.

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.

PMID:
25488815
PMCID:
PMC4288185
DOI:
10.1093/nar/gku1294
[Indexed for MEDLINE]
Free PMC Article

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