Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
J Biol Chem
2012 Dec 07;28750:42206-22. doi: 10.1074/jbc.M112.385674.
Show Gene links
Show Anatomy links
Targeting protein for xenopus kinesin-like protein 2 (TPX2) regulates γ-histone 2AX (γ-H2AX) levels upon ionizing radiation.
Neumayer G, Helfricht A, Shim SY, Le HT, Lundin C, Belzil C, Chansard M, Yu Y, Lees-Miller SP, Gruss OJ, van Attikum H, Helleday T, Nguyen MD.
???displayArticle.abstract???
The microtubule-associated protein targeting protein for Xenopus kinesin-like protein 2 (TPX2) plays a key role in spindle assembly and is required for mitosis in human cells. In interphase, TPX2 is actively imported into the nucleus to prevent its premature activity in microtubule organization. To date, no function has been assigned to nuclear TPX2. We now report that TPX2 plays a role in the cellular response to DNA double strand breaks induced by ionizing radiation. Loss of TPX2 leads to inordinately strong and transient accumulation of ionizing radiation-dependent Ser-139-phosphorylated Histone 2AX (γ-H2AX) at G(0) and G(1) phases of the cell cycle. This is accompanied by the formation of increased numbers of high intensity γ-H2AX ionizing radiation-induced foci. Conversely, cells overexpressing TPX2 have reduced levels of γ-H2AX after ionizing radiation. Consistent with a role for TPX2 in the DNA damage response, we found that the protein accumulates at DNA double strand breaks and associates with the mediator of DNA damage checkpoint 1 (MDC1) and the ataxia telangiectasia mutated (ATM) kinase, both key regulators of γ-H2AX amplification. Pharmacologic inhibition or depletion of ATM or MDC1, but not of DNA-dependent protein kinase (DNA-PK), antagonizes the γ-H2AX phenotype caused by TPX2 depletion. Importantly, the regulation of γ-H2AX signals by TPX2 is not associated with apoptosis or the mitotic functions of TPX2. In sum, our study identifies a novel and the first nuclear function for TPX2 in the cellular responses to DNA damage.
Aguirre-Portolés,
Tpx2 controls spindle integrity, genome stability, and tumor development.
2012,
Pubmed Arbour,
Mcl-1 is a key regulator of apoptosis during CNS development and after DNA damage.
2008,
Pubmed Asteriti,
The Aurora-A/TPX2 complex: a novel oncogenic holoenzyme?
2010,
Pubmed Bakkenist,
DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation.
2003,
Pubmed Berger,
Quantitative analysis of conditional gene inactivation using rationally designed, tetracycline-controlled miRNAs.
2010,
Pubmed Boleti,
Xklp2, a novel Xenopus centrosomal kinesin-like protein required for centrosome separation during mitosis.
1996,
Pubmed
,
Xenbase Brooks,
DNA repair in neural cells: basic science and clinical implications.
2002,
Pubmed Cha,
Wip1 directly dephosphorylates gamma-H2AX and attenuates the DNA damage response.
2010,
Pubmed Chang,
The TPX2 gene is a promising diagnostic and therapeutic target for cervical cancer.
2012,
Pubmed Chowdhury,
A PP4-phosphatase complex dephosphorylates gamma-H2AX generated during DNA replication.
2008,
Pubmed Cowell,
gammaH2AX foci form preferentially in euchromatin after ionising-radiation.
2007,
Pubmed DeLuca,
hNuf2 inhibition blocks stable kinetochore-microtubule attachment and induces mitotic cell death in HeLa cells.
2002,
Pubmed Douglas,
Protein phosphatase 6 interacts with the DNA-dependent protein kinase catalytic subunit and dephosphorylates gamma-H2AX.
2010,
Pubmed Durocher,
The FHA domain in DNA repair and checkpoint signaling.
2000,
Pubmed Eyers,
A novel mechanism for activation of the protein kinase Aurora A.
2003,
Pubmed
,
Xenbase Garrett,
hTPX2 is required for normal spindle morphology and centrosome integrity during vertebrate cell division.
2002,
Pubmed
,
Xenbase Gietz,
Screening for protein-protein interactions in the yeast two-hybrid system.
2002,
Pubmed Gietz,
Large-scale high-efficiency yeast transformation using the LiAc/SS carrier DNA/PEG method.
2007,
Pubmed Giunta,
DNA damage signaling in response to double-strand breaks during mitosis.
2010,
Pubmed Goldberg,
MDC1 is required for the intra-S-phase DNA damage checkpoint.
2003,
Pubmed Gruss,
Chromosome-induced microtubule assembly mediated by TPX2 is required for spindle formation in HeLa cells.
2002,
Pubmed
,
Xenbase Gruss,
The mechanism of spindle assembly: functions of Ran and its target TPX2.
2004,
Pubmed Gruss,
Ran induces spindle assembly by reversing the inhibitory effect of importin alpha on TPX2 activity.
2001,
Pubmed
,
Xenbase Guo,
Nudel contributes to microtubule anchoring at the mother centriole and is involved in both dynein-dependent and -independent centrosomal protein assembly.
2006,
Pubmed Harrison,
Surviving the breakup: the DNA damage checkpoint.
2006,
Pubmed Heidebrecht,
p100: a novel proliferation-associated nuclear protein specifically restricted to cell cycle phases S, G2, and M.
1997,
Pubmed Jänicke,
Caspase-3 is required for DNA fragmentation and morphological changes associated with apoptosis.
1998,
Pubmed Joukov,
The BRCA1/BARD1 heterodimer modulates ran-dependent mitotic spindle assembly.
2006,
Pubmed
,
Xenbase Kagawa,
Deficiency of caspase-3 in MCF7 cells blocks Bax-mediated nuclear fragmentation but not cell death.
2001,
Pubmed Kahana,
Cell cycle. Some importin news about spindle assembly.
2001,
Pubmed
,
Xenbase Karsenti,
TPX or not TPX?
2005,
Pubmed
,
Xenbase Khanna,
ATM, a central controller of cellular responses to DNA damage.
2001,
Pubmed Khanna,
DNA double-strand breaks: signaling, repair and the cancer connection.
2001,
Pubmed Kim,
Heterochromatin is refractory to gamma-H2AX modification in yeast and mammals.
2007,
Pubmed Kim,
Signaling networks controlled by the MRN complex and MDC1 during early DNA damage responses.
2006,
Pubmed Kurz,
DNA damage-induced activation of ATM and ATM-dependent signaling pathways.
2004,
Pubmed Lee,
Structure of the BRCT repeat domain of MDC1 and its specificity for the free COOH-terminal end of the gamma-H2AX histone tail.
2005,
Pubmed Lengauer,
Genetic instabilities in human cancers.
1998,
Pubmed Li,
Expression of targeting protein for Xenopus kinesin-like protein 2 is associated with progression of human malignant astrocytoma.
2010,
Pubmed
,
Xenbase Liang,
Nudel modulates kinetochore association and function of cytoplasmic dynein in M phase.
2007,
Pubmed Lou,
MDC1 maintains genomic stability by participating in the amplification of ATM-dependent DNA damage signals.
2006,
Pubmed Lou,
MDC1 is coupled to activated CHK2 in mammalian DNA damage response pathways.
2003,
Pubmed MacPhail,
Cell cycle-dependent expression of phosphorylated histone H2AX: reduced expression in unirradiated but not X-irradiated G1-phase cells.
2003,
Pubmed Macůrek,
Wip1 phosphatase is associated with chromatin and dephosphorylates gammaH2AX to promote checkpoint inhibition.
2010,
Pubmed Manda,
Identification of genes (SPON2 and C20orf2) differentially expressed between cancerous and noncancerous lung cells by mRNA differential display.
1999,
Pubmed Massip,
Deciphering the chromatin landscape induced around DNA double strand breaks.
2010,
Pubmed Matsuoka,
ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage.
2007,
Pubmed Maxwell,
Interplay between BRCA1 and RHAMM regulates epithelial apicobasal polarization and may influence risk of breast cancer.
2011,
Pubmed McManus,
ATM-dependent DNA damage-independent mitotic phosphorylation of H2AX in normally growing mammalian cells.
2005,
Pubmed Moon,
Wild-type p53-induced phosphatase 1 dephosphorylates histone variant gamma-H2AX and suppresses DNA double strand break repair.
2010,
Pubmed Mori,
An essential role of the aPKC-Aurora A-NDEL1 pathway in neurite elongation by modulation of microtubule dynamics.
2009,
Pubmed Nakada,
PP4 is a gamma H2AX phosphatase required for recovery from the DNA damage checkpoint.
2008,
Pubmed Negrini,
Genomic instability--an evolving hallmark of cancer.
2010,
Pubmed Neumann,
Phenotypic profiling of the human genome by time-lapse microscopy reveals cell division genes.
2010,
Pubmed Nguyen,
A NUDEL-dependent mechanism of neurofilament assembly regulates the integrity of CNS neurons.
2004,
Pubmed Peng,
Deficiency in the catalytic subunit of DNA-dependent protein kinase causes down-regulation of ATM.
2005,
Pubmed Pramparo,
Global developmental gene expression and pathway analysis of normal brain development and mouse models of human neuronal migration defects.
2011,
Pubmed Ramakrishna,
Identification of candidate growth promoting genes in ovarian cancer through integrated copy number and expression analysis.
2010,
Pubmed Rass,
Defective DNA repair and neurodegenerative disease.
2007,
Pubmed Satow,
Combined functional genome survey of therapeutic targets for hepatocellular carcinoma.
2010,
Pubmed Schatz,
Importin alpha-regulated nucleation of microtubules by TPX2.
2003,
Pubmed
,
Xenbase Shim,
Protein 600 is a microtubule/endoplasmic reticulum-associated protein in CNS neurons.
2008,
Pubmed Shim,
Ndel1 controls the dynein-mediated transport of vimentin during neurite outgrowth.
2008,
Pubmed Shu,
Ndel1 operates in a common pathway with LIS1 and cytoplasmic dynein to regulate cortical neuronal positioning.
2004,
Pubmed Sii-Felice,
Role of Fanconi DNA repair pathway in neural stem cell homeostasis.
2008,
Pubmed Sillars-Hardebol,
TPX2 and AURKA promote 20q amplicon-driven colorectal adenoma to carcinoma progression.
2012,
Pubmed Slee,
Benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethylketone (Z-VAD.FMK) inhibits apoptosis by blocking the processing of CPP32.
1996,
Pubmed Smeenk,
The NuRD chromatin-remodeling complex regulates signaling and repair of DNA damage.
2010,
Pubmed Stewart,
MDC1 is a mediator of the mammalian DNA damage checkpoint.
2003,
Pubmed Stewart,
Solving the RIDDLE of 53BP1 recruitment to sites of damage.
2009,
Pubmed Stiff,
ATM and DNA-PK function redundantly to phosphorylate H2AX after exposure to ionizing radiation.
2004,
Pubmed Stucki,
MDC1 directly binds phosphorylated histone H2AX to regulate cellular responses to DNA double-strand breaks.
2005,
Pubmed Stucki,
MDC1/NFBD1: a key regulator of the DNA damage response in higher eukaryotes.
2004,
Pubmed Stucki,
gammaH2AX and MDC1: anchoring the DNA-damage-response machinery to broken chromosomes.
2006,
Pubmed Tonon,
High-resolution genomic profiles of human lung cancer.
2005,
Pubmed Townsend,
Mediator of DNA damage checkpoint 1 (MDC1) regulates mitotic progression.
2009,
Pubmed van Attikum,
Crosstalk between histone modifications during the DNA damage response.
2009,
Pubmed van Attikum,
The histone code at DNA breaks: a guide to repair?
2005,
Pubmed Vanneste,
The role of Hklp2 in the stabilization and maintenance of spindle bipolarity.
2009,
Pubmed Vergnolle,
Cenp-F links kinetochores to Ndel1/Nde1/Lis1/dynein microtubule motor complexes.
2007,
Pubmed Warner,
Validation of TPX2 as a potential therapeutic target in pancreatic cancer cells.
2009,
Pubmed Wittmann,
TPX2, A novel xenopus MAP involved in spindle pole organization.
2000,
Pubmed
,
Xenbase Wittmann,
Localization of the kinesin-like protein Xklp2 to spindle poles requires a leucine zipper, a microtubule-associated protein, and dynein.
1998,
Pubmed
,
Xenbase Zhu,
BRCA1 tumour suppression occurs via heterochromatin-mediated silencing.
2011,
Pubmed
