title: SIRT1 and LSD1 competitively regulate KU70 functions in DNA repair and mutation acquisition in cancer cells.
abstract: Acquisition of BCR-ABL mutations underlies drug resistance of chronic myeloid leukemia (CML) to tyrosine kinase inhibitors, but the molecular mechanisms of mutation acquisition are poorly understood. We previously showed that lysine deacetylase sirtuin 1, SIRT1, promotes acquisition of BCR-ABL mutations in association with enhancing KU70 mediated non-homologous end joining DNA repair. In this study, we demonstrate that lysine specific demethylase 1 (LSD1) plays an opposite role to SIRT1 in regulating DNA repair and mutation acquisition. In response to therapeutic stress and DNA damage, LSD1 and SIRT1 compete for binding to KU70 on DNA damage foci globally and on the ABL locus. The recruitment of SIRT1 or LSD1 to KU70 impacts chromatin structure but does not correlate well with their direct histone modification functions, and SIRT1 helps maintain histone H4K16 acetylation and open chromatin for repair. The competitive KU70 binding by these proteins affects cancer cells' ability to repair broken DNA and acquire resistant genetic mutations in CML and prostate cancer cells. We identify that the core domain of KU70 binds both LSD1 and SIRT1, forming a molecular basis for the competition. The C-terminal SAP motif of KU70 mediates LSD1/SIRT1 competitive interaction by suppressing LSD1 binding to KU70 and ectopic expression of SAP-deleted KU70 to CML cells compromises their ability to acquire BCR-ABL mutations. Our study reveals a novel cellular stress response mechanism in cancer cells and a key role of LSD1/SIRT1/KU70 dynamic interaction in regulating DNA repair and mutation acquisition.
authors.affiliation: Department of Cancer Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
authors.forename: Mendel
authors.initials: M
authors.lastname: Roth
authors.affiliation: Department of Cancer Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Cancer Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
authors.forename: Wen Yong
authors.initials: WY
authors.lastname: Chen
mesh_terms: D020816:Amino Acid Motifs; D045744:Cell Line, Tumor; D004249:DNA Damage; D059766:DNA End-Joining Repair; D004260:DNA Repair; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic; D056466:Histone Demethylases / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D000072200:Ku Autoantigen / Q000378:metabolism*; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D000072417:Protein Domains; D056564:Sirtuin 1 / Q000378:metabolism*
chemical_list: C581634:BCR-ABL1 fusion protein, human; D056466:Histone Demethylases; C495195:KDM1A protein, human; D016044:Fusion Proteins, bcr-abl; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D000072200:Ku Autoantigen
keywords: BCR-ABL; NHEJ; chronic myeloid leukemia; lysine deacetylase; lysine demethylase