SIRT1 and LSD1 competitively regulate KU70 functions in DNA repair and mutation acquisition in cancer cells
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Mendel Roth1,*, Zhiqiang Wang1,*, Wen Yong Chen1
1Department of Cancer Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
*These authors have contributed equally to this work
Wen Yong Chen, email: firstname.lastname@example.org
Keywords: chronic myeloid leukemia, BCR-ABL, NHEJ, lysine deacetylase, lysine demethylase
Received: July 17, 2015 Accepted: June 13, 2016 Published: June 30, 2016
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.
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