title: Mechanisms and consequences of ATMIN repression in hypoxic conditions: roles for p53 and HIF-1.
abstract: Hypoxia-induced replication stress is one of the most physiologically relevant signals known to activate ATM in tumors. Recently, the ATM interactor (ATMIN) was identified as critical for replication stress-induced activation of ATM in response to aphidicolin and hydroxyurea. This suggests an essential role for ATMIN in ATM regulation during hypoxia, which induces replication stress. However, ATMIN also has a role in base excision repair, a process that has been demonstrated to be repressed and less efficient in hypoxic conditions. Here, we demonstrate that ATMIN is dispensable for ATM activation in hypoxia and in contrast to ATM, does not affect cell survival and radiosensitivity in hypoxia. Instead, we show that in hypoxic conditions ATMIN expression is repressed. Repression of ATMIN in hypoxia is mediated by both p53 and HIF-1α in an oxygen dependent manner. The biological consequence of ATMIN repression in hypoxia is decreased expression of the target gene, DYNLL1. An expression signature associated with p53 activity was negatively correlated with DYNLL1 expression in patient samples further supporting the p53 dependent repression of DYNLL1. Together, these data demonstrate multiple mechanisms of ATMIN repression in hypoxia with consequences including impaired BER and down regulation of the ATMIN transcriptional target, DYNLL1.
authors.affiliation: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, The University of Oxford, Oxford, OX3 7DQ, UK.
authors.forename: Katarzyna B
authors.initials: KB
authors.lastname: Leszczynska
authors.affiliation: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, The University of Oxford, Oxford, OX3 7DQ, UK.
authors.forename: Eva-Leonne
authors.initials: EL
authors.lastname: Göttgens
authors.affiliation: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, The University of Oxford, Oxford, OX3 7DQ, UK.
authors.forename: Deborah
authors.initials: D
authors.lastname: Biasoli
authors.affiliation: Division of Cancer and Radiation Oncology, Department of Radiation Oncology, Stanford University, Stanford, California 94305, USA.
authors.forename: Monica M
authors.initials: MM
authors.lastname: Olcina
authors.affiliation: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, The University of Oxford, Oxford, OX3 7DQ, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Ient
authors.affiliation: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, The University of Oxford, Oxford, OX3 7DQ, UK.
authors.forename: Selvakumar
authors.initials: S
authors.lastname: Anbalagan
authors.affiliation: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, The University of Oxford, Oxford, OX3 7DQ, UK.
authors.forename: Stephan
authors.initials: S
authors.lastname: Bernhardt
authors.affiliation: Division of Cancer and Radiation Oncology, Department of Radiation Oncology, Stanford University, Stanford, California 94305, USA.
authors.forename: Amato J
authors.initials: AJ
authors.lastname: Giaccia
authors.affiliation: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, The University of Oxford, Oxford, OX3 7DQ, UK.
authors.forename: Ester M
authors.initials: EM
authors.lastname: Hammond
mesh_terms: D015687:Cell Hypoxia; D002460:Cell Line; D056445:Cytoplasmic Dyneins / Q000096:biosynthesis; D005786:Gene Expression Regulation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: C522841:ATMIN protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C427758:DYNLL1 protein, human; D056445:Cytoplasmic Dyneins