title: The co-repressor SMRT delays DNA damage-induced caspase activation by repressing pro-apoptotic genes and modulating the dynamics of checkpoint kinase 2 activation.
abstract: Checkpoint kinase 2 (Chk2) is a major regulator of DNA damage response and can induce alternative cellular responses: cell cycle arrest and DNA repair or programmed cell death. Here, we report the identification of a new role of Chk2 in transcriptional regulation that also contributes to modulating the balance between survival and apoptosis following DNA damage. We found that Chk2 interacts with members of the NCoR/SMRT transcriptional co-regulator complexes and serves as a functional component of the repressor complex, being required for recruitment of SMRT on the promoter of pro-apoptotic genes upon DNA damage. Thus, the co-repressor SMRT exerts a critical protective action against genotoxic stress-induced caspase activation, repressing a functionally important cohort of pro-apoptotic genes. Amongst them, SMRT is responsible for basal repression of Wip1, a phosphatase that de-phosphorylates and inactivates Chk2, thus affecting a feedback loop responsible for licensing the correct timing of Chk2 activation and the proper execution of the DNA repair process.
authors.affiliation: Howard Hughes Medical Institute and School of Medicine, University of California San Diego, La Jolla, California, United States of America. cscafoglio@mednet.ucla.edu
authors.forename: Claudio
authors.initials: C
authors.lastname: Scafoglio
authors.forename: Marcus
authors.initials: M
authors.lastname: Smolka
authors.forename: Huilin
authors.initials: H
authors.lastname: Zhou
authors.forename: Valentina
authors.initials: V
authors.lastname: Perissi
authors.forename: Michael G
authors.initials: MG
authors.lastname: Rosenfeld
mesh_terms: D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D064447:Checkpoint Kinase 2 / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D004249:DNA Damage / Q000502:physiology*; D004789:Enzyme Activation / Q000502:physiology; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D046228:Microarray Analysis; D056985:Nuclear Receptor Co-Repressor 2 / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D000071636:Protein Phosphatase 2C; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D056985:Nuclear Receptor Co-Repressor 2; D064447:Checkpoint Kinase 2; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C