title: Phosphorylation-Dependent Enhancement of Rad53 Kinase Activity through the INO80 Chromatin Remodeling Complex.
abstract: ATP-dependent chromatin remodeling complexes such as INO80 have been implicated in checkpoint regulation in response to DNA damage. However, how chromatin remodeling complexes regulate DNA damage checkpoints remain unclear. Here, we identified a mechanism of regulating checkpoint effector kinase Rad53 through a direct interaction with the INO80 chromatin remodeling complex. Rad53 is a key checkpoint kinase downstream of Mec1. Mec1/Tel1 phosphorylates the Ies4 subunit of the INO80 complex in response to DNA damage. We find that the phosphorylated Ies4 binds to the N-terminal FHA domain of Rad53. In vitro, INO80 can activate Rad53 kinase activity in an Ies4-phosphorylation-dependent manner in the absence of known activators such as Rad9. In vivo, Ies4 and Rad9 function synergistically to activate Rad53. These findings establish a direct connection between ATP-dependent chromatin remodeling complexes and checkpoint regulation.
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, Science Park Research Division, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA.
authors.forename: Prabodh
authors.initials: P
authors.lastname: Kapoor
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, Science Park Research Division, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA.
authors.forename: Yunhe
authors.initials: Y
authors.lastname: Bao
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, Science Park Research Division, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, Science Park Research Division, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA.
authors.forename: Alexsandra
authors.initials: A
authors.lastname: Espejo
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, Science Park Research Division, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Bedford
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Guang
authors.initials: G
authors.lastname: Peng
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, Science Park Research Division, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA. Electronic address: snowshen@mac.com.
authors.forename: Xuetong
authors.initials: X
authors.lastname: Shen
mesh_terms: D000595:Amino Acid Sequence; D018797:Cell Cycle Proteins / Q000378:metabolism*; D064447:Checkpoint Kinase 2 / Q000378:metabolism*; D004789:Enzyme Activation; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D012441:Saccharomyces cerevisiae / Q000201:enzymology*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism* / Q000502:physiology*
chemical_list: D018797:Cell Cycle Proteins; C483404:INO80 complex, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D064447:Checkpoint Kinase 2; C067022:RAD53 protein, S cerevisiae