ATR and ATRIP: Partners in Checkpoint Signaling

Chen, David; Guntuku, Saritha; Qin, Jun; Elledge, Stephen J.

doi:10.1126/science.1065521

Cited by 888 publications

(833 citation statements)

References 21 publications

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“…The PIKK-interaction domain on Nbs1 was originally shown by Jackson and co-workers to be analogous to a similar domain on ATR-interacting protein (ATRIP) that is important for the association with ATR (Falck et al, 2005). ATRIP does not seem to function in the same manner as Nbs1, however, because ATRIP is constitutively bound to ATR and seems to primarily function in the recruitment of ATR to RPAbound DNA (Cortez et al, 2001). …”

Section: Role Of the C-terminus Of Nbs1mentioning

confidence: 99%

Activation and regulation of ATM kinase activity in response to DNA double-strand breaks

2007

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The ataxia-telangiectasia-mutated (ATM) protein kinase is rapidly and specifically activated in response to DNA double-strand breaks in eukaryotic cells. In this review, we summarize recent insights into the mechanism of ATM activation, focusing on the role of the Mre11/Rad50/Nbs1 (MRN) complex in this process. We also compare observations of the ATM activation process in different biological systems and highlight potential candidates for cellular factors that may participate in regulating ATM activity in human cells.

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Section: Role Of the C-terminus Of Nbs1mentioning

confidence: 99%

Activation and regulation of ATM kinase activity in response to DNA double-strand breaks

2007

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“…Whereas, at the sites of double strand breaks (DSB) the DNA damage sensor complex, MRN (Mre11-Rad50-Nbs1) assembles (van den Bosch et al, 2003;Petrini and Stracker, 2003). In addition, there is evidence that supports ATRIP (ATR interacting partner) being a DNA damage sensory protein, which specifically recognises RPA coated ssDNA independently of Rad17 and 9-1-1 complexes (Zou and Elledge, 2000;Cortez et al, 2001). Another proposed sensory protein is Claspin (although it shows mediator properties), which is also found to associate with ssDNA created by stalled replication forks independently of RPA and Rad17 Lee et al, 2003).…”

Section: Endpointsmentioning

confidence: 99%

An ATM- and ATR-dependent checkpoint inactivates spindle assembly by targeting CEP63

Smith¹,

Dejsuphong

Balestrini³

et al. 2009

Nat Cell Biol

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The effects of ATM and ATR signalling induced by chromosomal breakage have been described extensively in modulating cell cycle progression up to the onset of mitosis.However, DNA damage checkpoint responses in mitotic cells are not well understood.This thesis reports on the effects of double strand breaks on the progression of mitosis.We found ATM and ATR activation can occur in mitotic Xenopus laevis egg extract and the induction of ATM and ATR by chromosomal breakages inhibits spindle assembly in both Xenopus egg extract and somatic cells. The delay in mitotic progression induced by ATM and ATR was found not to involve major spindle assembly factors activities such as, Cdk1, Plx1 and RCC1/Ran-GTP. However, normal anastral spindles formation around linear DNA coated beads, which can activate ATM and ATR, linked centrosome-driven spindle assembly to ATM and ATR dependent spindle defects. cDNA expression library screening was undertaken to identify novel ATM and ATR targets in this mitotic checkpoint pathway, through which the novel centrosomal protein XCEP63 was identified as a likely candidate. Data obtained from depletion and reconstitution of XCEP63 in Xenopus egg extract established that normal centrosome-driven spindle assembly requires XCEP63. Moreover, ATM and ATR phosphorylates XCEP63 on serine 560 and promotes delocalisation from the centrosome. ATM and ATR inhibition or addition of non-phosphorylable XCEP63 recombinant protein mutated at serine 560 prevents spindle assembly abnormalities.These findings suggest that ATM and ATR regulate mitotic events by targeting XCEP63 and centrosome-dependent spindle assembly. This pathway may provide support for DNA repair processes or regulate cell survival in the presence of mitotic DNA damage. 3

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“…On the other hand, ATR regulates the cellular response to ultraviolet (UV) radiationinduced damage and stalled DNA replication forks and also participates in the late response to IR (Tibbetts et al, 1999;Guo et al, 2000). Activation of ATR proceeds through its association with ATR-interacting protein (Cortez et al, 2001). More recently, an additional PIKK family member termed hSMG-1 or ATX was also shown to regulate cell cycle checkpoints in response to IR and UV irradiation (Brumbaugh et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

hSMG-1 and ATM sequentially and independently regulate the G1 checkpoint during oxidative stress

et al. 2008

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Genotoxic stress activates the phosphatidylinositol 3-kinase-like kinases (PIKKs) that phosphorylate proteins involved in cell cycle arrest, DNA repair and apoptosis. Previous work showed that the PIKK ataxia telangiectasia mutated (ATM) but not ATM and Rad3 related phosphorylates p53 (Ser15) during hyperoxia, a model of prolonged oxidative stress and DNA damage. Here, we show hSMG-1 is responsible for the rapid and early phosphorylation of p53 (Ser15) and that ATM helps maintain phosphorylation after 24 h. Despite reduced p53 phosphorylation and abundance in cells depleted of hSMG-1 or ATM, levels of the p53 target p21 were still elevated and the G 1 checkpoint remained intact. Conditional overexpression of p21 in p53-deficient cells revealed that hyperoxia also stimulates wortmannin-sensitive degradation of p21. siRNA depletion of hSMG-1 or ATM restored p21 stability and the G 1 checkpoint during hyperoxia. These findings establish hSMG-1 as a proximal regulator of DNA damage signaling and reveal that the G 1 checkpoint is tightly regulated during prolonged oxidative stress by both PIKK-dependent synthesis and proteolysis of p21.

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ATR and ATRIP: Partners in Checkpoint Signaling

Cited by 888 publications

References 21 publications

Activation and regulation of ATM kinase activity in response to DNA double-strand breaks

Activation and regulation of ATM kinase activity in response to DNA double-strand breaks

An ATM- and ATR-dependent checkpoint inactivates spindle assembly by targeting CEP63

hSMG-1 and ATM sequentially and independently regulate the G1 checkpoint during oxidative stress

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