title: LKB1 preserves genome integrity by stimulating BRCA1 expression.
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.
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Romi
authors.initials: R
authors.lastname: Gupta
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Alex Y
authors.initials: AY
authors.lastname: Liu
authors.affiliation: Department of Therapeutic Radiology and Genetics, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Glazer
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA narendra.wajapeyee@yale.edu.
authors.forename: Narendra
authors.initials: N
authors.lastname: Wajapeyee
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D002453:Cell Cycle; D002460:Cell Line; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D051959:ELAV Proteins / Q000378:metabolism; D016678:Genome; D006801:Humans; D051379:Mice; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism; D059767:Recombinational DNA Repair
chemical_list: D019313:BRCA1 Protein; D051959:ELAV Proteins; D012333:RNA, Messenger; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases