Cell cycle checkpoint signaling through the ATM and ATR kinases

In the paper

“Our own results indicate that hSMG1 is found in both the nucleus and cytoplasm, and, like ATM and ATR, exhibits phosphotransferase activity toward a variety of proteins containing Ser-Gln motifs under in vitro assay conditions.”

In the paper

“However, members of the Rad group of checkpoint proteins, which include Rad17, Rad1, Rad9, Rad26, and Hus1 (nomenclature based on the Schizosaccharomyces pombe gene products) are widely expressed in all eukaryotic cells, and are prime suspects in the lineup of candidate DNA damage sensors (Green et al. 2000;O'Connell et al. 2000).”

What the sources say

• Not checked yetcites Green et al. 2000
• Not checked yetcites O'Connell et al. 2000

In the paper

“On the other hand, mTOR plays no identifiable role in genome surveillance; rather, this PIKK coordinates G 1 phase progression with the supply of nutrients and growth factors (Gingras et al. 2001).”

What the sources say

• Not checked yetcites Gingras et al. 2001

In the paper

“The catalytic subunit of DNA-dependent protein kinase (DNA-PK cs ) functions as a heterotrimeric complex containing two Ku subunits (Ku-70 and Ku-80), and makes its own crucial contribution to genome maintenance by overseeing the nonhomologous end-joining (NHEJ) pathway of DNA double-strand break (dsb) repair (Smith and Jackson 1999).”

What the sources say

• Not checked yetcites Smith and Jackson 1999

In the paper

“Interestingly, yet another member of the Rad family, Rad17, bears homology to the RFC subunits and, in fact, associates with RFC subunits to form a putative checkpoint clamp loading complex (CLC) that governs the interaction of the Rad1-Rad9-Hus1 CSC with damaged DNA (Green et al. 2000;O'Connell et al. 2000).”

What the sources say

• Not checked yetcites Green et al. 2000
• Not checked yetcites O'Connell et al. 2000

In the paper

“Three of these Rad proteins, Rad1, Rad9, and Hus1, exhibit structural similarity to the proliferating cell nuclear antigen (PCNA), and accumulating evidence supports the idea that this similarity may extend to function as well (Thelen et al. 1999;Burtelow et al. 2000).”

What the sources say

• Not checked yetcites Thelen et al. 1999
• Not checked yetcites Burtelow et al. 2000

In the paper

“Immune complex kinase assays quickly revealed that, like DNA-PK, ATM and ATR displayed S/T-Q-directed kinase activities under in vitro conditions, and that a physiologically relevant substrate for both protein kinases was p53 (Banin et al. 1998;Canman et al. 1998;Tibbetts et al. 1999;Ziv et al. 2000).”

What the sources say

• Not checked yetcites Banin et al. 1998
• Not checked yetcites Canman et al. 1998
• Not checked yetcites Tibbetts et al. 1999

In the paper

“Collectively, these results hint that ATM and ATR respond to DNA damage in fundamentally different fashions: One checkpoint kinase (ATM) becomes catalytically active, whereas the other (ATR) redistributes into DNA damage-induced nuclear foci, where it presumably gains access to its substrates.”

In the paper

“These efforts identified a consensus phosphorylation site [(M/F)-(Q/P)-L-S-Q-(E/Q)] that was in reasonable agreement with that defined by Kastan and coworkers (Kim et al. 1999).Remarkably, the relatively unbiased peptide selection strategy zeroed in on a core L-S-Q-E target sequence, which was identical to that surrounding the Ser 15 site in p53.”

What the sources say

• Not checked yetcites O'Neill et al. 2000
• Not checked yetcites Kim et al. 1999

In the paper

“The latter complex plays impor-tant roles in the recombinational repair of DNA dsbs, and the loss of one of the components of this complex, NBS1, gives rise to the Nijmegen breakage syndrome, a chromosomal instability disorder that bears several similarities to A-T (Shiloh 1997).”

What the sources say

• Not checked yetcites Shiloh 1997

In the paper

“Many of these foci react with both ATR-and BRCA1-specific antibodies, suggesting that the two proteins colocalize at sites of DNA damage.”

What the sources say

• Not checked yetcites Scully et al. 1997
• Not checked yetcites Tibbetts et al. 2000

In the paper

“The breast cancer susceptibility protein, BRCA1, is a critical component of the checkpoint signaling and DNA repair machinery, and is a direct target for phosphorylation by ATM and ATR in cells exposed to genotoxic stress (Cortez et al. 1999;Scully and Livingston 2000;Scully et al. 2000;Tibbetts et al. 2000).”

What the sources say

• Not checked yetcites Cortez et al. 1999
• Not checked yetcites Scully and Livingston 2000
• Not checked yetcites Tibbetts et al. 2000

In the paper

“In cells rendered functionally deficient for ATR by overexpression of a kinase-inactive ATR KI mutant (Cliby et al. 1998), the early phase (0-2 h) of IR-induced p53 phosphorylation was not impaired, which is consistent with the idea that ATM serves as the major Ser 15 kinase during the acute response to IR”

What the sources say

• Not checked yetcites Tibbetts et al. 1999

In the paper

“Moreover, phosphorylation of Ser 15 was rapidly induced in IR-treated cells, and this response was ATM dependent, as IR-induced Ser 15 phosphorylation was significantly, but not completely, suppressed in A-T cells”

What the sources say

• Not checked yetcites Siliciano et al. 1997
• Not checked yetcites Banin et al. 1998
• Not checked yetcites Canman et al. 1998

In the paper

“However, the ATR KI -overexpressing cells did show a significant defect in their ability to maintain phosphorylation of Ser 15 at later times, which suggests that the maintenance phase of p53 phosphorylation was more highly dependent on ATR.”

What the sources say

• Not checked yetcites Tibbetts et al. 1999

In the paper

“On the other hand, treatment of human fibroblasts with UV light triggered a Ser 15 phosphorylation response that was largely independent of ATM expression, and was strongly reduced, at all times postirradiation, by overexpression of ATR KI”

What the sources say

• Not checked yetcites Tibbetts et al. 1999

In the paper

“It turns out, however, that Ser 15 phosphorylation is not sufficient to disrupt the p53-MDM2 interaction; rather, this modification stimulates the transactivating function of p53 by enhancing the binding of this protein to the transcriptional coactivator, p300”

What the sources say

• Not checked yetcites Dumaz and Meek 1999

In the paper

“In the absence of ATM, or in normal cells that incur a high level of IR-induced DNA damage, ATR serves mainly as a backup kinase for ATM.”

In the paper

“Unlike the Ser 15 modification mentioned earlier, phosphorylation at Ser 20 interferes directly with the binding of p53 to MDM2, thereby favoring p53 accumulation in response to IR-induced DNA damage.”

In the paper

“In the absence of ATM, the IR-induced decrease in DNA synthesis is dampened significantly, giving rise to the RDS phenotype.”

What the sources say

• Not checked yetcites Painter and Young 1980

In the paper

“Remarkably, mutant hChk2 alleles associated with a variant form of Li-Fraumeni syndrome (Bell et al. 1999) failed to bind and/or phosphorylate Cdc25A (Falck et al. 2001), which implies that genetic lesions in the RDS pathway promote genome instability and cancer development.”

What the sources say

• Not checked yetcites Falck et al. 2001
• Not checked yetcites Bell et al. 1999

In the paper

“The results obtained by Falck et al. (2001) show that hChk2 phosphorylates Ser 123 in Cdc25A, and that this modification targets Cdc25A for ubiquitin-dependent degradation.”

What the sources say

• Not checked yetcites Falck et al. 2001

In the paper

“The appearance of these foci is dependent on the expression of NBS1; however, the absence of major DNA repair defects in cells from NBS patients indicates that the Mre11-Rad50 complex carries out its repair functions quite capably in NBS1-deficient cells”

What the sources say

• Not checked yetcites Petrini 1999

In the paper

“ATM phosphorylates NBS1 on up to three serine residues (Ser 343, Ser 397, and Ser 615), and that Ser → Ala substitutions at any one of these sites generated a mutant NBS1 protein that failed to complement the checkpoint defects in NBS cells”

What the sources say

• Not checked yetcites Gatei et al. 2000b
• Not checked yetcites Lim et al. 2000
• Not checked yetcites Wu et al. 2000

In the paper

“Treatment of cells with IR induces the rapid formation of nuclear foci containing the NBS1-Mre11-Rad50 complex, and a technologically elegant study offered strong evidence that the foci assemble in close proximity to DNA dsbs”

What the sources say

• Not checked yetcites Nelms et al. 1998

In the paper

“With the caveat in mind that overexpressed ATR KI may nonspecifically cross-inhibit ATM function, these results suggest either that ATR also resides upstream of hChk2, or that ATR regulates a parallel pathway that contributes to the suppression of DNA synthesis in IR-damaged cells.”

In the paper

“Interestingly, NBS cells also display the RDS phenotype, which suggests that the NBS1 protein is an upstream regulator of Cdc25A stability in IR-treated cells.”

In the paper

“Cortez et al. (1999) observed that the phosphorylation of BRCA1 in IR-damaged cells was significantly impaired in the absence of ATM, and demonstrated that at least five of the predicted S-Q target sites in the SCD were phosphorylated by ATM in vitro.”

What the sources say

• Not checked yetcites Cortez et al. 1999

In the paper

“The carboxy-terminal region of BRCA1 contains numerous S-Q motifs (total of 14), and, of these potential ATM/ATR target sequences, 10 are localized in an ∼300 amino acid stretch (residues 1250-1550) termed the SQ cluster domain (SCD)”

What the sources say

• Not checked yetcites Cortez et al. 1999

In the paper

“In contrast to ATR, ATM seems dedicated to providing the cell with a rapid protective response to an extremely lethal form of DNA damage, the DNA dsb.”

In the paper

“it is likely that, outside of the laboratory setting, the intrinsic accoutrements of life as a multicellular organism, such as continuous assaults by oxygen-derived radicals, and the need to generate a diverse repertoire of antigen-responsive lymphocytes, generated evolutionary pressure for the development of a checkpoint signaling module geared toward sounding the DNA dsb alarm at the first sign”

In the paper

“The pathway is governed primarily by ATR, and may use members of the Rad family of checkpoint proteins as damage sensors and as scaffolds for the assembly of checkpoint signaling complexes.”

In the paper

“The checkpoint response leads to the proteosome-mediated degradation of Cdc25A, and, in turn, the failure to maintain activation of cyclin•cdk2 complexes and a resultant inhibition of DNA synthesis.”

In the paper

“Both branches converge on the Cdc25C phosphatase, and prevent activation of the mitotic cyclin B•cdc2 complex by inducing the cytoplasmic sequestration and/or catalytic inhibition of Cdc25C.”