title: Possible involvement of LKB1-AMPK signaling in non-homologous end joining.
abstract: LKB1/STK11 is a tumor suppressor gene responsible for Peutz-Jeghers syndrome, an inherited cancer disorder associated with genome instability. The LKB1 protein functions in the regulation of cell proliferation, polarization and differentiation. Here, we suggest a role of LKB1 in non-homologous end joining (NHEJ), a major DNA double-strand break (DSB) repair pathway. LKB1 localized to DNA ends upon the generation of micro-irradiation and I-SceI endonuclease-induced DSBs. LKB1 inactivation either by RNA interference or by kinase-dead mutation compromised NHEJ-mediated DNA repair by suppressing the accumulation of BRM, a catalytic subunit of the SWI/SNF complex, at DSB sites, which promotes the recruitment of an essential NHEJ factor, KU70. AMPK2, a major substrate of LKB1 and a histone H2B kinase, was recruited to DSBs in an LKB1-dependent manner. AMPK2 depletion and a mutation of H2B that disrupted the AMPK2 phoshorylation site impaired KU70 and BRM recruitment to DSB sites. LKB1 depletion induced the formation of chromosome breaks and radials. These results suggest that LKB1-AMPK signaling controls NHEJ and contributes to genome stability.
authors.affiliation: 1] Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan [2] Division of Dynamic Proteome, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Ui
authors.affiliation: Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Ogiwara
authors.affiliation: Department of Molecular Genetics, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Nakajima
authors.affiliation: Division of Dynamic Proteome, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Kanno
authors.affiliation: Division of Dynamic Proteome, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Watanabe
authors.affiliation: Laboratory of Molecular Biology, Division of Life Science, Department of Molecular and Cell Biology, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Harata
authors.affiliation: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: H
authors.initials: H
authors.lastname: Okayama
authors.affiliation: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: C C
authors.initials: CC
authors.lastname: Harris
authors.affiliation: Division of Multistage Carcinogenesis, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Yokota
authors.affiliation: 1] Division of Dynamic Proteome, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan [2] Department of Molecular Genetics, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Yasui
authors.affiliation: Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kohno
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly; D059766:DNA End-Joining Repair; D016147:Genes, Tumor Suppressor; D042822:Genomic Instability; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection
chemical_list: D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases