Site-specific Phosphorylation Dynamics of the Nuclear Proteome during the DNA Damage Response

Bennetzen, Martin V.; Larsen, Dorthe Helena; Bunkenborg, Jakob; Bártek, Jiří; Lukáš, Jiří; Andersen, Jens S.

doi:10.1074/mcp.m900616-mcp200

Cited by 228 publications

(239 citation statements)

References 44 publications

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“…In this work we have used motif-specific IAE and MS to assess known DDR phosphorylation events (13,14,29,30) while simultaneously interrogating signals unique to this model in which coadministration of GDC-0973 with GDC-0941 has proven efficacious (Fig. 4D and Dataset S3) (17,18).…”

Section: Discussionmentioning

confidence: 99%

Phosphoproteomic characterization of DNA damage response in melanoma cells following MEK/PI3K dual inhibition

Kirkpatrick¹,

Bustos²,

Dogan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Section: Discussionmentioning

confidence: 99%

Phosphoproteomic characterization of DNA damage response in melanoma cells following MEK/PI3K dual inhibition

Kirkpatrick¹,

Bustos²,

Dogan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Despite a putative ATM target motif (S-Q) in the ARIH1 protein at serine 514, phosphorylation of this site has not been detected by us or by other groups in the presence or absence of genotoxic stress (3,61,62; unpublished data) (http: //www.phosphosite.org). Although this may also be an outcome of technical limitations of the MS used in these studies (for example, a very short tryptic fragment), it points to an indirect mechanism by which ATM signaling leads to ARIH1 accumulation after genotoxic stress.…”

Section: Discussionmentioning

confidence: 99%

The E3 Ubiquitin Ligase ARIH1 Protects against Genotoxic Stress by Initiating a 4EHP-Mediated mRNA Translation Arrest

Stechow

Typas

Carreras-Puigvert

et al. 2015

Molecular and Cellular Biology

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bDNA damage response signaling is crucial for genome maintenance in all organisms and is corrupted in cancer. In an RNA interference (RNAi) screen for (de)ubiquitinases and sumoylases modulating the apoptotic response of embryonic stem (ES) cells to DNA damage, we identified the E3 ubiquitin ligase/ISGylase, ariadne homologue 1 (ARIH1). Silencing ARIH1 sensitized ES and cancer cells to genotoxic compounds and ionizing radiation, irrespective of their p53 or caspase-3 status. Expression of wild-type but not ubiquitinase-defective ARIH1 constructs prevented sensitization caused by ARIH1 knockdown. ARIH1 protein abundance increased after DNA damage through attenuation of proteasomal degradation that required ATM signaling. Accumulated ARIH1 associated with 4EHP, and in turn, this competitive inhibitor of the eukaryotic translation initiation factor 4E (eIF4E) underwent increased nondegradative ubiquitination upon DNA damage. Genotoxic stress led to an enrichment of ARIH1 in perinuclear, ribosome-containing regions and triggered 4EHP association with the mRNA 5= cap as well as mRNA translation arrest in an ARIH1-dependent manner. Finally, restoration of DNA damage-induced translation arrest in ARIH1-depleted cells by means of an eIF2 inhibitor was sufficient to reinstate resistance to genotoxic stress. These findings identify ARIH1 as a potent mediator of DNA damage-induced translation arrest that protects stem and cancer cells against genotoxic stress. DNA damage leads to acute toxicity and the accumulation of mutations and chromosomal instability, potentially resulting in malignant transformation (1, 2). To counteract these deleterious effects of DNA damage, the cell is equipped with a highly complex signaling response termed the DNA damage response (DDR). The DDR activates effector components involved in protective pathways, including DNA damage repair, cell cycle arrest, transcription regulation, chromatin remodeling, and cell death (1). The complex of DDR signaling pathways is crucial for the protection of the genome in all organisms. Moreover, understanding DDR signaling in the context of chemical or ionizing radiation-induced DNA damage is important to design improved strategies to combat therapy resistance. In tandem with phosphorylation-mediated signaling, which is largely executed by the phosphoinositol 3-kinase (PI3K)-like kinases ATM, ATR, and DNA-dependent protein kinase (DNA-PK), the checkpoint kinases Chk1 and Chk2, and members of the mitogen-activated protein kinase (MAPK) family (3, 4), protein modifications by ubiquitin and ubiquitin-like moieties are crucial at all levels of the DDR (5).The ubiquitination machinery can form various, differentially interpreted tags, including both degradative (K48-and K11-linked chains) and nondegradative (monoubiquitination and K63-linked chains) signals (6). Furthermore, a growing family of ubiquitin-like modifications, such as SUMO, Nedd8, and ISG15, has been identified, mostly providing nondegradative signals. Multiple enzymes are shared between the ubiquitinat...

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“…This simplistic view, however, is in fact more complex because DSBs are processed during the S/G 2 phases of the cell cycle by the endonuclease CtIP and generate single-stranded DNA lesions leading to a secondary activation of the ATR (Jazayeri et al, 2006;Sartori et al, 2007). All phosphatidylinositol-3-OH kinases responding to DNA damage show similar substrate specificities, and recent phosphoproteomic screens reveal a substantial overlap of their substrates (Matsuoka et al, 2007;Bennetzen et al, 2010;Bensimon et al, 2010). The best example is probably the histone variant H2AX, which is rapidly phosphorylated at Ser-139 (producing gH2AX) by ATM/ATR or DNA-PK in the chromatin flanking the damage site.…”

Section: Activation Of Dna-damage Checkpointsmentioning

confidence: 99%

Checkpoint control and cancer

2011

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DNA-damaging therapies represent the most frequently used non-surgical anticancer strategies in the treatment of human tumors. These therapies can kill tumor cells, but at the same time they can be particularly damaging and mutagenic to healthy tissues. The efficacy of DNAdamaging treatments can be improved if tumor cell death is selectively enhanced, and the recent application of poly-(ADP-ribose) polymerase inhibitors in BRCA1/2-deficient tumors is a successful example of this. DNA damage is known to trigger cell-cycle arrest through activation of DNA-damage checkpoints. This arrest can be reversed once the damage has been repaired, but irreparable damage can promote apoptosis or senescence. Alternatively, cells can reenter the cell cycle before repair has been completed, giving rise to mutations. In this review we discuss the mechanisms involved in the activation and inactivation of DNA-damage checkpoints, and how the transition from arrest and cell-cycle re-entry is controlled. In addition, we discuss recent attempts to target the checkpoint in anticancer strategies.

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Site-specific Phosphorylation Dynamics of the Nuclear Proteome during the DNA Damage Response

Cited by 228 publications

References 44 publications

Phosphoproteomic characterization of DNA damage response in melanoma cells following MEK/PI3K dual inhibition

Phosphoproteomic characterization of DNA damage response in melanoma cells following MEK/PI3K dual inhibition

The E3 Ubiquitin Ligase ARIH1 Protects against Genotoxic Stress by Initiating a 4EHP-Mediated mRNA Translation Arrest

Checkpoint control and cancer

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