The CHK2–BRCA1 tumour suppressor pathway ensures chromosomal stability in human somatic cells

Stolz, Ailine; Ertych, Norman; Kienitz, Anne; Vogel, Celia; Schneider, Verena; Fritz, Bárbara; Jacob, Ralf; Dittmar, Gunnar; Weichert, Wilko; Petersen, Iver; Bastians, Holger

doi:10.1038/ncb2051

Cited by 142 publications

(186 citation statements)

References 32 publications

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“…41 Recently, Chk2 was shown to be necessary for proper mitosis progression. 42 Chk2 may compensate for the depletion of Chk1 in mouse oocytes shown in this study. Additionally, Chk1 flox mice were generated, 43 and oocyte specific Chk1 conditional knockout mice may be generated to provide in vivo information about functions of Chk1 in meiosis.…”

Section: Discussionmentioning

confidence: 97%

Checkpoint kinase 1 is essential for meiotic cell cycle regulation in mouse oocytes

et al. 2012

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Section: Discussionmentioning

confidence: 97%

Checkpoint kinase 1 is essential for meiotic cell cycle regulation in mouse oocytes

et al. 2012

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“…That phosphorylation of the ATR target Chk1 was not promoted by ectopic CycG2 expression suggests that CycG2 overexpression did not activate ATR. Recent work indicates that pChk2(Thr-68) serves a DNA damage-independent function during mitosis to ensure proper spindle assembly and maintain chromosomal stability (54,55). The kinases PLK1, TTK/hMps1, and DNA-PK can each interact with and phosphorylate Chk2 on Thr-68 and play DDR-independent roles in regulating mitosis and spindle assembly checkpoints (43, 52, 56 -58).…”

Section: Discussionmentioning

confidence: 99%

Elevated Cyclin G2 Expression Intersects with DNA Damage Checkpoint Signaling and Is Required for a Potent G2/M Checkpoint Arrest Response to Doxorubicin

Zimmermann

Arachchige-Don

Donaldson

et al. 2012

Journal of Biological Chemistry

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Background: DNA damage triggers cell cycle checkpoints to halt cell division ahead of DNA repair. Results: Ectopic cyclin G2 (CycG2) induces a Chk2-dependent cell cycle arrest, and depletion of endogenous CycG2 attenuates doxorubicin-induced G 2 /M-phase cell cycle arrest. Conclusion: CycG2 influences checkpoint signaling and is required for G 2 /M arrest responses to genotoxic stress. Significance: Proper checkpoint function is important for genomic integrity and tumor suppression.

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“…19 In addition, in collaboration with BRCA1, and independently of p53, CHK2 is required for the normal progression of mitosis and chromosomal stability. 20,21 Although Chk2 is phosphorylated and activated primarily by the kinase ATM, it is also ubiquitylated; however, the mechanism of this ubiquitylation remains poorly understood. 11 In this study, we report that PIRH2 interacts with CHK2 and mediates its polyubiquitylation and proteasomal degradation.…”

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confidence: 99%

The E3 ligase PIRH2 polyubiquitylates CHK2 and regulates its turnover

et al. 2013

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The serine threonine kinase checkpoint kinase 2 (CHK2) is a DNA damage checkpoint protein important for the ATM-p53 signaling pathway. In addition to its phosphorylation, CHK2 is also ubiquitylated, and both post-translational modifications are important for its function. However, although the mechanisms that regulate CHK2 phosphorylation are well established, those that control its ubiquitylation are not fully understood. In this study, we demonstrate that the ubiquitin E3 ligase PIRH2 (p53-induced protein with a RING (Really Interesting New Gene)-H2 domain) interacts with CHK2 and mediates its polyubiquitylation and proteasomal degradation. We show that the deubiquitylating enzyme USP28 forms a complex with PIRH2 and CHK2 and antagonizes PIRH2-mediated polyubiquitylation and proteasomal degradation of CHK2. We also provide evidence that CHK2 ubiquitylation by PIRH2 is dependent on its phosphorylation status. Cells deficient in Pirh2 displayed accumulation of Chk2 and enhanced hyperactivation of G1/S and G2/M cell-cycle checkpoints. This hyperactivation was, however, no longer observed in Pirh2 PIRH2 (p53-induced protein with a RING (Really Interesting New Gene)-H2 domain), also known as RCHY1, encodes for an ubiquitin (Ub) ligase that is transcriptionally regulated by p53.1 PIRH2 interacts with the active tetrameric form of p53, mediates its ubiquitylation and regulates its turnover via Ubproteasome mechanisms.1,2 PIRH2 exerts its ubiquitylation function in cooperation with the E2 Ub-conjugating enzyme UbcH5b.1 A recent study indicated that PIRH2 negative regulation of p53 is enhanced in the presence of the ubiquitylation factor E4B.3 In addition to p53, other ubiquitylation substrates have been also reported for PIRH2, including c-Myc, 4 p27kip1, 5 e-COP, 6 the signal recognition particle receptor b subunit, 7 the DNA polymerase eta 8 and p73. 9,10The serine threonine kinase CHK2 (checkpoint kinase 2) is a checkpoint effector important for the signaling of DNA double-strand breaks and the activation of cell-cycle checkpoints.11 In response to DNA damage, ataxia telangiectasia mutated (ATM) phosphorylates CHK2 on its threonine 68 (T68) and allows it to interact with the FHA domain of another CHK2.12-14 This dimerization of CHK2 leads to its autophosphorylation on T383 and T387 and promotes its full activation.15-17 CHK2 phosphorylates p53 on Serine 20 (S23 for mouse) in response to DNA damage and has also other phosphorylation substrates, including PML, E2F1, CDC25C and BRCA1, highlighting its importance in processes such as DNA repair, cell-cycle arrest, apoptosis and senescence.18 CHK2 is also involved in DNA repair via the phosphorylation of Forkhead Box M1. 19 In addition, in collaboration with BRCA1, and independently of p53, CHK2 is required for the normal progression of mitosis and chromosomal stability. 20,21Although Chk2 is phosphorylated and activated primarily by the kinase ATM, it is also ubiquitylated; however, the mechanism of this ubiquitylation remains poorly understood.11 In this study, we rep...

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The CHK2–BRCA1 tumour suppressor pathway ensures chromosomal stability in human somatic cells

Cited by 142 publications

References 32 publications

Checkpoint kinase 1 is essential for meiotic cell cycle regulation in mouse oocytes

Checkpoint kinase 1 is essential for meiotic cell cycle regulation in mouse oocytes

Elevated Cyclin G2 Expression Intersects with DNA Damage Checkpoint Signaling and Is Required for a Potent G2/M Checkpoint Arrest Response to Doxorubicin

The E3 ligase PIRH2 polyubiquitylates CHK2 and regulates its turnover

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