DDB1 Targets Chk1 to the Cul4 E3 Ligase Complex in Normal Cycling Cells and in Cells Experiencing Replication Stress

Leung-Pineda, Van; Huh, Jimi; Piwnica‐Worms, Helen

doi:10.1158/0008-5472.can-08-3382

Cited by 112 publications

(150 citation statements)

References 54 publications

Supporting

Mentioning

142

Contrasting

Order By: Relevance

“…These results suggest that SFKs are capable of suppressing ATR-mediated Chk1 phosphorylation via a mechanism other than Claspin degradation. Although we did not investigate whether SFK inhibition perturbs Chk1 dephosphorylation or degradation (25)(26)(27)(28)(29)(30), these data suggest that SFKs regulate ATR signaling via ATRdependent Rad17 phosphorylation.…”

Section: Sfk Activity Is Required For G 2 Dna Damage Checkpointmentioning

confidence: 84%

“…Claspin mediates the ATR-dependent phosphorylation of Chk1 to activate the ATR-Chk1 signaling pathway (20). Following checkpoint activation, several protein phosphatases and ubiquitin ligases target the activated checkpoint proteins including Rad17 (21), Claspin (22)(23)(24), and Chk1 (25)(26)(27)(28)(29)(30). The direct dephosphorylation and degradation of checkpoint proteins promote the termination of checkpoint signaling (1)(2)(3).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Src Family Kinases Promote Silencing of ATR-Chk1 Signaling in Termination of DNA Damage Checkpoint

Fukumoto

Morii

Miura

et al. 2014

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: Once DNA repair is completed, the DNA damage checkpoint is terminated, and the cell cycle is resumed. Results: Src inhibition induced a delay in G 2 checkpoint recovery and persistent ATR-Chk1 activation. Conclusion: Src inhibits ATR signaling to promote recovery from G 2 checkpoint arrest. Significance: Src sends a termination signal between the completion of DNA repair and the initiation of checkpoint termination.

show abstract

Section: Sfk Activity Is Required For G 2 Dna Damage Checkpointmentioning

confidence: 84%

mentioning

confidence: 99%

Src Family Kinases Promote Silencing of ATR-Chk1 Signaling in Termination of DNA Damage Checkpoint

Fukumoto

Morii

Miura

et al. 2014

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Previous studies have shown that Chk1 is degraded by the ubiquitinproteasome system and that this can be stimulated by phosphorylation of the protein at S345 (18)(19)(20)(21)(22). Because we had observed a decrease in phospho-Chk1 at earlier time points after Atg7 recombination, we reasoned this may be due to enhanced degradation of the protein, which over time would then have an impact on the total pool of Chk1 under conditions where DNA-damage signaling would be enhanced after a prolonged loss of autophagy.…”

Section: Significancementioning

confidence: 84%

Loss of autophagy causes a synthetic lethal deficiency in DNA repair

Liu

O’Prey

et al. 2015

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

140

113

View full text Add to dashboard Cite

(Macro)autophagy delivers cellular constituents to lysosomes for degradation. Although a cytoplasmic process, autophagy-deficient cells accumulate genomic damage, but an explanation for this effect is currently unclear. We report here that inhibition of autophagy causes elevated proteasomal activity leading to enhanced degradation of checkpoint kinase 1 (Chk1), a pivotal factor for the errorfree DNA repair process, homologous recombination (HR). We show that loss of autophagy critically impairs HR and that autophagy-deficient cells accrue micronuclei and sub-G1 DNA, indicators of diminished genomic integrity. Moreover, due to impaired HR, autophagy-deficient cells are hyperdependent on nonhomologous end joining (NHEJ) for repair of DNA double-strand breaks. Consequently, inhibition of NHEJ following DNA damage in the absence of autophagy results in persistence of genomic lesions and rapid cell death. Because autophagy deficiency occurs in several diseases, these findings constitute an important link between autophagy and DNA repair and highlight a synthetic lethal strategy to kill autophagy-deficient cells.autophagy | DNA repair | cell death | synthetic lethality T he preservation of genome integrity is critical for the prevention of human disease. In addition, the maintenance of proteome integrity is also considered central to healthy cellular homeostasis. Macroautophagy, hereafter referred to as autophagy, is a process that is paramount in counteracting damage to cytoplasmic constituents (1). Upon initiation of autophagy, double-membraned vesicles termed "autophagosomes" form to encapsulate cargoes including damaged or misfolded proteins and organelles. These vesicles ultimately fuse with lysosomes and the acidic hydrolases provided by the lysosome degrade cargoes into constituent parts, which can be recycled into biosynthetic pathways or in some situations, further catabolized to produce energy for the cell (1). Autophagy functions at basal levels in virtually all cells and is a major mechanism for protein turnover and the only known mechanism for degradation of organelles (1). Due to its crucial role in maintaining cytoplasmic and therefore cellular homeostasis, perturbations in autophagy have been reported to be an important contributing factor in a spectrum of diseases, including Crohn's disease, lysosomal storage disorders, neurodegenerative diseases, and cancer (2-6).Autophagy operates in the cytoplasm and yet studies have shown that autophagy-deficient cells accumulate DNA damage (5). The reasons behind this observation, however, are not completely clear. Because the cellular environment of autophagy-deficient cells will cause accrual of damaged proteins with abnormal function and as a result accumulation of reactive oxygen species, it is easily conceivable that this will ultimately lead to a higher incidence of genetic lesions. However, even when autophagy is competent, our cells are already subject to an extremely high frequency of spontaneous DNA damage. The fact that this damage does not persist is ...

show abstract

“…Although we did observe DNA damage 3 days after And-1 depletion, we did not observe DNA damage in cells harvested 48 h after siRNA transfection (Supplementary Fig S3D). Given that DNA damage itself can induce Chk1 protein degradation (Zhang et al, 2005(Zhang et al, , 2009Leung-Pineda et al, 2009), it is possible that the degradation of Chk1 that was observed by Yoshizawa-Sugata et al resulted from DNA damage due to an extended period of And-1 depletion.…”

Section: Discussionmentioning

confidence: 99%

And‐1 coordinates with Claspin for efficient Chk1 activation in response to replication stress

Hao

Renty

et al. 2015

The EMBO Journal

View full text Add to dashboard Cite

The replisome is important for DNA replication checkpoint activation, but how specific components of the replisome coordinate with ATR to activate Chk1 in human cells remains largely unknown. Here, we demonstrate that And-1, a replisome component, acts together with ATR to activate Chk1. And-1 is phosphorylated at T826 by ATR following replication stress, and this phosphorylation is required for And-1 to accumulate at the damage sites, where And-1 promotes the interaction between Claspin and Chk1, thereby stimulating efficient Chk1 activation by ATR. Significantly, And-1 binds directly to ssDNA and facilitates the association of Claspin with ssDNA. Furthermore, And-1 associates with replication forks and is required for the recovery of stalled forks. These studies establish a novel ATR-And-1 axis as an important regulator for efficient Chk1 activation and reveal a novel mechanism of how the replisome regulates the replication checkpoint and genomic stability.

show abstract

DDB1 Targets Chk1 to the Cul4 E3 Ligase Complex in Normal Cycling Cells and in Cells Experiencing Replication Stress

Abstract: The Chk1 protein kinase preserves genome integrity in normal proliferating cells and in cells experiencing replicative and genotoxic stress. Chk1 is currently being targeted in anticancer regimens. Here, we identify damaged DNA-binding protein 1 (DDB1) as a novel Chk1-interacting protein.

Cited by 112 publications

References 54 publications

Src Family Kinases Promote Silencing of ATR-Chk1 Signaling in Termination of DNA Damage Checkpoint

Src Family Kinases Promote Silencing of ATR-Chk1 Signaling in Termination of DNA Damage Checkpoint

Loss of autophagy causes a synthetic lethal deficiency in DNA repair

And‐1 coordinates with Claspin for efficient Chk1 activation in response to replication stress

Contact Info

Product

Resources

About