title: LKB1 is a DNA damage response protein that regulates cellular sensitivity to PARP inhibitors.
abstract: Liver kinase B1 (LKB1) functions as a tumor suppressor encoded by STK11, a gene that mutated in Peutz-Jeghers syndrome and in sporadic cancers. Previous studies showed that LKB1 participates in IR- and ROS-induced DNA damage response (DDR). However, the impact of LKB1 mutations on targeted cancer therapy remains unknown. Herein, we demonstrated that LKB1 formed DNA damage-induced nuclear foci and co-localized with ataxia telangiectasia mutated kinase (ATM), γ-H2AX, and breast cancer susceptibility 1 (BRCA1). ATM mediated LKB1 phosphorylation at Thr 363 following the exposure of cells to ionizing radiation (IR). LKB1 interacted with BRCA1, a downstream effector in DDR that is recruited to sites of DNA damage and functions directly in homologous recombination (HR) DNA repair. LKB1 deficient cells exhibited delayed DNA repair due to insufficient HR. Notably, LKB1 deficiency sensitized cells to poly (ADP-ribose) polymerase (PARP) inhibitors. Thus, we have demonstrated a novel function of LKB1 in DNA damage response. Cancer cells lacking LKB1 are more susceptible to DNA damage-based therapy and, in particular, to drugs that further impair DNA repair, such as PARP inhibitors.
authors.affiliation: Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, Jilin 130021, China.
authors.forename: Yi-Shu
authors.initials: YS
authors.lastname: Wang
authors.affiliation: Division of Hematology and Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Chen
authors.affiliation: Division of Hematology and Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Fengmei
authors.initials: F
authors.lastname: Cui
authors.affiliation: Division of Hematology and Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Huibo
authors.initials: H
authors.lastname: Wang
authors.affiliation: Division of Hematology and Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Shuai
authors.initials: S
authors.lastname: Wang
authors.affiliation: Division of Hematology and Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Hang
authors.affiliation: Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, Jilin 130021, China.|Division of Hematology and Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Zeng
authors.affiliation: Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, Jilin 130021, China.
authors.forename: Cheng-Shi
authors.initials: CS
authors.lastname: Quan
authors.affiliation: Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, Jilin 130021, China.
authors.forename: Ying-Xian
authors.initials: YX
authors.lastname: Zhai
authors.affiliation: Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, Jilin 130021, China.
authors.forename: Jian-Wei
authors.initials: JW
authors.lastname: Wang
authors.affiliation: Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, Jilin 130021, China.
authors.forename: Xiang-Feng
authors.initials: XF
authors.lastname: Shen
authors.affiliation: Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, Jilin 130021, China.
authors.forename: Yong-Ping
authors.initials: YP
authors.lastname: Jian
authors.affiliation: Division of Hematology and Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Rui-Xun
authors.initials: RX
authors.lastname: Zhao
authors.affiliation: Division of Hematology and Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Kaitlin D
authors.initials: KD
authors.lastname: Werle
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Boston University, School of Medicine, Boston, MA 02118, USA.
authors.forename: Rutao
authors.initials: R
authors.lastname: Cui
authors.affiliation: Department of Systems Biology, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jiyong
authors.initials: J
authors.lastname: Liang
authors.affiliation: Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, Jilin 130021, China.
authors.forename: Yu-Lin
authors.initials: YL
authors.lastname: Li
authors.affiliation: Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, Jilin 130021, China.|Division of Hematology and Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Zhi-Xiang
authors.initials: ZX
authors.lastname: Xu
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D019313:BRCA1 Protein / Q000378:metabolism; D045744:Cell Line, Tumor; D004249:DNA Damage; D004260:DNA Repair; D019008:Drug Resistance, Neoplasm; D059765:Homologous Recombination; D006801:Humans; D010766:Phosphorylation; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D021381:Protein Transport
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases
keywords: DNA damage; LKB1; PARP inhibitor; homologous recombination; sensitization