LKB1 preserves genome integrity by stimulating BRCA1 expression

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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*

Substances

  • BRCA1 Protein
  • ELAV Proteins
  • RNA, Messenger
  • Protein Serine-Threonine Kinases
  • STK11 protein, human
  • AMP-Activated Protein Kinase Kinases
  • AMP-Activated Protein Kinases