Centrosomal Chk2 in DNA damage responses and cell cycle progession

Golan, Amnon; Pick, Elah; Tsvetkov, Lyuben; Nadler, Yasmine; Kluger, Harriet M.; Stern, David F.

doi:10.4161/cc.9.13.12121

Cited by 23 publications

(16 citation statements)

References 29 publications

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“…Centrosomes are known to integrate many regulatory factors that control cell cycle progression and DDR. Cell cycle regulators such as Cdk-cyclin complex (Bailly et al, 1992; Hinchcliffe et al, 1999), Chk1 (Kramer et al, 2004; Zhang et al, 2007) and Chk2 (Golan et al, 2010; Hong and Stambrook, 2004; Zhang et al, 2007) are present on centrosomes. Furthermore, DDR regulators such as ATM, ATR and DNA-PK have also been shown to reside on centrosomes (Zhang et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Filia Is an ESC-Specific Regulator of DNA Damage Response and Safeguards Genomic Stability

et al. 2015

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Summary Pluripotent stem cells (PSCs) hold great promise in cell-based therapy, but the genomic instability seen in culture hampers full application. Greater understanding of the factors that regulate genomic stability in PSCs could help address this issue. Here we describe the identification of Filia as a specific regulator of genomic stability in mouse embryonic stem cells (ESCs). Filia expression is induced by genotoxic stress. Filia promotes centrosome integrity and regulates DNA damage response (DDR) through multiple pathways, including DDR signaling, cell cycle checkpoints and damage repair, ESC differentiation and apoptosis. Filia depletion causes ESC genomic instability, induces resistance to apoptosis and promotes malignant transformation. As part of its role in the DDR, Filia interacts with PARP1 and stimulates its enzymatic activity. Filia also constitutively resides on centrosomes and translocates to DNA damage sites and mitochondria, consistent with its multifaceted roles in regulating centrosome integrity, damage repair and apoptosis.

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Section: Discussionmentioning

confidence: 99%

Filia Is an ESC-Specific Regulator of DNA Damage Response and Safeguards Genomic Stability

et al. 2015

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“…HA and Flag purifications of transfected cells or untransfected cells (mock), were performed, as previously described [53], [55]. After purification, part of HA-beads-bound complexes or mock were used for immunoblotting, and part were used for deneddylation assay.…”

Section: Methodsmentioning

confidence: 99%

The Minimal Deneddylase Core of the COP9 Signalosome Excludes the Csn6 MPN− Domain

Pick

Golan²,

Zimbler³

et al. 2012

PLoS ONE

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The COP9 signalosome (CSN) is a eukaryotic protein complex, which regulates a wide range of biological processes mainly through modulating the cullin ubiquitin E3 ligases in the ubiquitin-proteasome pathway. The CSN possesses a highly conserved deneddylase activity that centers at the JAMM motif of the Csn5 subunit but requires other subunits in a complex assembly. The classic CSN is composed of 8 subunits (Csn1–8), yet in several Ascomycota, the complex is smaller and lacks orthologs for a few CSN subunits, but nevertheless contains a conserved Csn5. This feature makes yeast a powerful model to determine the minimal assemblage required for deneddylation activity. Here we report, that Csi1, a diverged S. cerevisiae CSN subunit, displays significant homology with the carboxyl terminal domain of the canonical Csn6, but lacks the amino terminal MPN- domain. Through the comparative and experimental analyses of the budding yeast and the mammalian CSNs, we demonstrate that the MPN− domain of the canonical mouse Csn6 is not part of the CSN deneddylase core. We also show that the carboxyl domain of Csn6 has an indispensable role in maintaining the integrity of the CSN complex. The CSN complex assembled with the carboxyl fragment of Csn6, despite its lack of an MPN− domain, is fully active in deneddylation of cullins. We propose that the budding yeast Csi1 is a functional equivalent of the canonical Csn6, and thus the composition of the CSN across phyla is more conserved than hitherto appreciated.

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“…Alternatively, as CycG2 can interact and form complexes with PP2A B56 and C subunits (13,59) and phosphorylation of Chk2 on Thr-68 is negatively regulated by B56 isoforms of PP2A (60,61), it is possible that in otherwise unperturbed cells, overexpressed CycG2 acts as a PP2A sink and in so doing inhibits PP2A-mediated dephosphorylation of Chk2. In this context it is notable that CycG2, PP2A, and Chk2 all associate with centrosomes (15,62,63).…”

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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Centrosomal Chk2 in DNA damage responses and cell cycle progession

Cited by 23 publications

References 29 publications

Filia Is an ESC-Specific Regulator of DNA Damage Response and Safeguards Genomic Stability

Filia Is an ESC-Specific Regulator of DNA Damage Response and Safeguards Genomic Stability

The Minimal Deneddylase Core of the COP9 Signalosome Excludes the Csn6 MPN− Domain

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

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