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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The CTC1/STN1/TEN1 (CST) complex is an essential constituent of plant and vertebrate telomeres. Here we show that CST and ATR (ataxia telangiectasia mutated [ATM] and Rad3-related) act synergistically to maintain telomere length and genome stability in Arabidopsis. Inactivation of ATR, but not ATM, temporarily rescued severe morphological phenotypes associated with ctc1 or stn1. Unexpectedly, telomere shortening accelerated in plants lacking CST and ATR. In first-generation (G1) ctc1 atr mutants, enhanced telomere attrition was modest, but in G2 ctc1 atr, telomeres shortened precipitously, and this loss coincided with a dramatic decrease in telomerase activity in G2 atr mutants. Zeocin treatment also triggered a reduction in telomerase activity, suggesting that the prolonged absence of ATR leads to a hitherto-unrecognized DNA damage response (DDR). Finally, our data indicate that ATR modulates DDR in CST mutants by limiting chromosome fusions and transcription of DNA repair genes and also by promoting programmed cell death in stem cells. We conclude that the absence of CST in Arabidopsis triggers a multifaceted ATR-dependent response to facilitate maintenance of critically shortened telomeres and eliminate cells with severe telomere dysfunction.
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PMID:ATR cooperates with CTC1 and STN1 to maintain telomeres and genome integrity in Arabidopsis. 2235 13

Senescence stimuli activate multiple tumor suppressor pathways to initiate cycle arrest and a differentiation program characteristic of senescent cells. We performed a two-stage, gain-of-function screen to select for the genes whose enhanced expression can bypass replicative senescence. We uncovered multiple genes known to be involved in p53 and Rb regulation and ATM regulation, two components of the CST (CTC1-STN1-TEN1) complex involved in preventing telomere erosion, and genes such as REST and FOXO4 that have been implicated in aging. Among the new genes now implicated in senescence, we identified DLX2, a homeobox transcription factor that has been shown to be required for tumor growth and metastasis and is associated with poor cancer prognosis. Growth analysis showed that DLX2 expression led to increased cellular replicative life span. Our data suggest that DLX2 expression reduces the protein components of the TTI1/TTI2/TEL2 complex, a key complex required for the proper folding and stabilization of ATM and other members of the PIKK (phosphatidylinositol 3-kinase-related kinase) family kinase, leading to reduced ATM-p53 signaling and senescence bypass. We also found that the overexpression of DLX2 exhibited a mutually exclusive relationship with p53 alterations in cancer patients. Our functional screen identified novel players that may promote tumorigenesis by regulating the ATM-p53 pathway and senescence.
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PMID:A gain-of-function senescence bypass screen identifies the homeobox transcription factor DLX2 as a regulator of ATM-p53 signaling. 2683 29

Human CST (CTC1-STN1-TEN1) is an RPA-like complex that associates with G-rich single-strand DNA and helps resolve replication problems both at telomeres and genome-wide. We previously showed that CST binds and disrupts G-quadruplex (G4) DNA in vitro, suggesting that CST may prevent in vivo blocks to replication by resolving G4 structures. Here, we demonstrate that CST binds and unfolds G4 with similar efficiency to RPA. In cells, CST is recruited to telomeric and non-telomeric chromatin upon G4 stabilization, even when ATR/ATM pathways were inhibited. STN1 depletion increases G4 accumulation and slows bulk genomic DNA replication. At telomeres, combined STN1 depletion and G4 stabilization causes multi-telomere FISH signals and telomere loss, hallmarks of deficient telomere duplex replication. Strand-specific telomere FISH indicates preferential loss of C-strand DNA while analysis of BrdU uptake during leading and lagging-strand telomere replication shows preferential under-replication of lagging telomeres. Together these results indicate a block to Okazaki fragment synthesis. Overall, our findings indicate a novel role for CST in maintaining genome integrity through resolution of G4 structures both ahead of the replication fork and on the lagging strand template.
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PMID:Mammalian CST averts replication failure by preventing G-quadruplex accumulation. 3097 12

CST (CTC1-STN1-TEN1) is a heterotrimeric, RPA-like complex that binds to single-stranded DNA (ssDNA) and functions in the replication of telomeric and non-telomeric DNA. Previous studies demonstrated that deletion of CTC1 results in decreased cell proliferation and telomere DNA damage signaling. However, a detailed analysis of the consequences of conditional CTC1 knockout (KO) has not been fully elucidated. Here, we investigated the effects of CTC1 KO on cell cycle progression, genome-wide replication and activation of the DNA damage response. Consistent with previous findings, we demonstrate that CTC1 KO results in decreased cell proliferation, G2 arrest and RPA-bound telomeric ssDNA. However, despite the increased levels of telomeric RPA-ssDNA, global ATR-dependent CHK1 and p53 phosphorylation was not detected in CTC1 KO cells. Nevertheless, we show that RPA-ssDNA does activate ATR, leading to the phosphorylation of RPA and autophosphorylation of ATR. Further analysis determined that inactivation of ATR, but not CHK1 or ATM, suppressed the accumulation of G2 arrested cells and phosphorylated RPA following CTC1 removal. These results suggest that ATR is localized and active at telomeres but is unable to elicit a global checkpoint response through CHK1. Furthermore, CTC1 KO inhibited CHK1 phosphorylation following hydroxyurea-induced replication stress. Additional studies revealed that this suppression of CHK1 phosphorylation, following replication stress, is caused by decreased levels of the ATR activator TopBP1. Overall, our results identify CST as a novel regulator of the ATR-CHK1 pathway.
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PMID:Human CTC1 promotes TopBP1 stability and CHK1 phosphorylation in response to telomere dysfunction and global replication stress. 3326 65