Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

hCds1 (Chk2) is an evolutionarily conserved kinase that functions in DNA damage response and cell cycle checkpoint. The Cds1 family of kinases are activated by a family of large phosphatidylinositol 3-kinase-like kinases. In humans, ataxia telangiectasia-mutated (ATM) and ataxia-telangiectasia and Rad3-related kinases activate hCds1 by phosphorylating Thr(68) . hCds1 and Cds1-related kinases contain the FHA (forkhead-associated) domain, which appears to be important for integrating the DNA damage signal. It is not known how ATM phosphorylation activates hCds1 function and whether the phosphorylation is linked to the FHA. Here, we demonstrate that the hCds1-FHA domain is essential for Thr(68) phosphorylation. Thr(68) phosphorylation, in turn, is required for ionizing radiation-induced autophosphorylation of two amino acid residues in hCds1, Thr(383) and Thr(387). These two amino acid residues, located in the activation loop of hCds1, are conserved in hCds1-related kinases and are essential for hCds1 activity. Thus, the hCds1-FHA domain mediates a chain of phosphorylation events on hCds1, which includes phosphorylation by ATM and hCds1 autophosphorylation, in response to DNA damage.
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PMID:The hCds1 (Chk2)-FHA domain is essential for a chain of phosphorylation events on hCds1 that is induced by ionizing radiation. 1139 Apr 8

The Chk2 Ser/Thr kinase plays crucial, evolutionarily conserved roles in cellular responses to DNA damage. Identification of two pro-oncogenic mutations within the Chk2 FHA domain has highlighted its importance for Chk2 function in checkpoint activation. The X-ray structure of the Chk2 FHA domain in complex with an in vitro selected phosphopeptide motif reveals the determinants of binding specificity and shows that both mutations are remote from the peptide binding site. We show that the Chk2 FHA domain mediates ATM-dependent Chk2 phosphorylation and targeting of Chk2 to in vivo binding partners such as BRCA1 through either or both of two structurally distinct mechanisms. Although phospho-dependent binding is important for Chk2 activity, previously uncharacterized phospho-independent FHA domain interactions appear to be the primary target of oncogenic lesions.
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PMID:Structural and functional versatility of the FHA domain in DNA-damage signaling by the tumor suppressor kinase Chk2. 1204 40

NFBD1/KIAA0170 is a nuclear factor with an N-terminal FHA (forkhead-associated) domain and a tandem repeat of BRCT (breast cancer susceptibility gene-1 C terminus) domains, both of which are present in a number of proteins involved in DNA repair and/or DNA damage signaling pathways. We have investigated the association of NFBD1 with DNA damage responses. We found that the NFBD1 transcript is abundant in the testis relative to other tissues. NFBD1 is a chromatin-associated protein and is modified in G(2)/M phase or after DNA damage. NFBD1 phosphorylation in response to ionizing radiation (IR) was ATM-dependent. NFBD1 exhibited diffuse nuclear staining in the majority of untreated cells analyzed by indirect immunofluorescence and formed discrete nuclear foci after exposure to IR, UV radiation, and hydroxyurea treatment. IR induced NFBD1 foci within 1 min. The foci colocalized with gamma-H2AX foci, which have been previously shown to localize at sites of DNA double-strand breaks. IR-induced NFBD1 foci also colocalized with 53BP1 and MRE11/RAD50 foci. Taken together, these results suggest that NFBD1 is a mediator of DNA damage-dependent signaling.
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PMID:NFBD1/KIAA0170 is a chromatin-associated protein involved in DNA damage signaling pathways. 1249 69

NFBD1/MDC1 (mediator of DNA damage checkpoint 1) is a nuclear factor with an amino-terminal FHA (forkhead-associated) domain and a tandem repeat of BRCT (breast cancer susceptibility gene-1 carboxyl terminus) domains. We have previously shown that NFBD1 is an early participant in DNA damage signaling pathways and that ionizing radiation-induced nuclear foci (IRIF) of NFBD1 colocalize with several DNA checkpoint signaling and repair factors. We report here that NFBD1 physically associates with ATM, p53, components of the MRE11-RAD50-NBS1 (MRN) complex, and gamma-H2AX. An overexpressed FHA domain-containing fragment of NFBD1 binds to endogenous NFBD1 and components of the MRN complex, but not to gamma-H2AX. This fragment interferes with IRIF formation by endogenous NFBD1, MRE11, or NBS1. A BRCT domain-containing fragment of NFBD1 binds to gamma-H2AX and 53BP1, but not to components of the MRN complex, and abolishes IRIF formation by NFBD1, MRE11, NBS1, 53BP1, CHK2 phospho-T68, gamma-H2AX, and possible ATM/ATR substrates recognized by anti-phospho-SQ/TQ antibody. These results suggest that NFBD1 is an ATM/ATR-dependent organizer that recruits DNA checkpoint signaling and repair proteins to the sites of DNA damage.
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PMID:NFBD1/MDC1 regulates ionizing radiation-induced focus formation by DNA checkpoint signaling and repair factors. 1451 63

The ATM kinase is a tumour suppressor and a key activator of genome integrity checkpoints in mammalian cells exposed to ionizing radiation (IR) and other insults that elicit DNA double-strand breaks (DSBs). In response to IR, autophosphorylation on serine 1981 causes dissociation of ATM dimers and initiates cellular ATM kinase activity. Here, we show that the kinetics and magnitude of ATM Ser1981 phosphorylation after exposure of human fibroblasts to low doses (2 Gy) of IR are altered in cells deficient in Nbs1, a substrate of ATM and a component of the MRN (Mre11-Rad50-Nbs1) complex involved in processing/repair of DSBs and ATM-dependent cell cycle checkpoints. Timely phosphorylation of both ATM Ser1981 and the ATM substrate Smc1 after IR were rescued via retrovirally mediated reconstitution of Nbs1-deficient cells by wild-type Nbs1 or mutants of Nbs1 defective in the FHA domain or nonphosphorylatable by ATM, but not by Nbs1 lacking the Mre11-interaction domain. Our data indicate that apart from its role downstream of ATM in the DNA damage checkpoint network, the MRN complex serves also as a modulator/amplifier of ATM activity. Although not absolutely required for ATM activation, the MRN nuclease complex may help reach the threshold activity of ATM necessary for optimal genome maintenance and prevention of cancer.
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PMID:Distinct functional domains of Nbs1 modulate the timing and magnitude of ATM activation after low doses of ionizing radiation. 1504 89

Mdc1/NFBD1 controls cellular responses to DNA damage, in part via interacting with the Mre11-Rad50-Nbs1 complex that is involved in the recognition, signalling, and repair of DNA double-strand breaks (DSBs). Here, we show that in live human cells, the transient interaction of Nbs1 with DSBs and its phosphorylation by ATM are Mdc1-independent. However, ablation of Mdc1 by siRNA or mutation of the Nbs1's FHA domain required for Mdc1 binding reduced the affinity of Nbs1 for DSB-flanking chromatin and caused aberrant pan-nuclear dispersal of Nbs1. This occurred despite normal phosphorylation of H2AX, indicating that lack of Mdc1 does not impair this DSB-induced chromatin change, but rather precludes the sustained engagement of Nbs1 with these regions. Mdc1 (but not Nbs1) became partially immobilized to chromatin after DSB generation, and siRNA-mediated depletion of H2AX prevented such relocalization of Mdc1 and uncoupled Nbs1 from DSB-flanking chromatin. Our data suggest that Mdc1 functions as an H2AX-dependent interaction platform enabling a switch from transient, Mdc1-independent recruitment of Nbs1 to DSBs towards sustained, Mdc1-dependent interactions with the surrounding chromosomal microenvironment.
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PMID:Mdc1 couples DNA double-strand break recognition by Nbs1 with its H2AX-dependent chromatin retention. 1520 65

The isolation of the NBS1 gene revealed the molecular mechanisms of DSB repair. In response to DNA damage, histone H2AX in the vicinity of DSBs is phosphorylated by ATM. NBS1 then targets the MRE11/RAD50 complex to the sites of DSBs through interaction of the FHA/BRCT domain with gamma-H2AX. NBSI complex binds to damaged-DNA directly, and HR repair is initiated. To collaborate DSB repair, ATM also regulates cell cycle checkpoints at GI, G2, and intra-S phases via phosphorylation of SMC, CHK2 and FANCD2. The phosphorylation of these proteins require NBS1 complex. Thus, NBSI has at least two important roles in genome maintenance, as a DNA repair protein in HR pathway and as a signal modifier in intra-S phase checkpoints. NBSI is also known to be involved in maintenance of telomores, which have DSB-like structures and defects here can cause telomcric fusion. Therefore, NBS1 should be a multi-functional protein for the maintenance of genomic integrity. Further studies on NBS1 will provide insights into the mechanisms of DNA damage response and the network of these factors involved in genomic stability.
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PMID:Nijmegen breakage syndrome and DNA double strand break repair by NBS1 complex. 1547 93

The isolation of the NBS1 gene revealed the molecular mechanisms of DSB repair. In response to DNA damage, histone H2AX in the vicinity of DSBs is phosphorylated by ATM. NBS1 then targets the MRE11/RAD50 complex to the sites of DSBs through interaction of the FHA/BRCT domain with gamma-H2AX. NBS1 complex binds to damaged-DNA directly, and HR repair is initiated. To collaborate DSB repair, ATM also regulates cell cycle checkpoints at G1, G2, and intra-S phases via phosphorylation of SMC, CHK2 and FANCD2. The phosphorylation of these proteins require NBS1 complex. Thus, NBS1 has at least two important roles in genome maintenance, as a DNA repair protein in HR pathway and as a signal modifier in intra-S phase checkpoints. NBS1 is also known to be involved in maintenance of telomeres, which have DSB-like structures and defects here can cause telomeric fusion. Therefore, NBS1 should be a multifunctional protein for the maintenance of genomic integrity. Further studies on NBS1 will provide insights into the mechanisms of DNA damage response and the network of these factors involved in genomic stability.
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PMID:Nijmegen breakage syndrome and DNA double strand break repair by NBS1 complex. 1549 28

MDC1 functions in checkpoint activation and DNA repair following DNA damage. To address the physiological role of MDC1, we disrupted the MDC1 gene in mice. MDC1-/- mice recapitulated many phenotypes of H2AX-/- mice, including growth retardation, male infertility, immune defects, chromosome instability, DNA repair defects, and radiation sensitivity. At the molecular level, H2AX, MDC1, and ATM form a positive feedback loop, with MDC1 directly mediating the interaction between H2AX and ATM. MDC1 binds phosphorylated H2AX through its BRCT domain and ATM through its FHA domain. Through these interactions, MDC1 accumulates activated ATM flanking the sites of DNA damage, facilitating further ATM-dependent phosphorylation of H2AX and the amplification of DNA damage signals. In the absence of MDC1, many downstream ATM signaling events are defective. These results suggest that MDC1, as a signal amplifier of the ATM pathway, is vital in controlling proper DNA damage response and maintaining genomic stability.
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PMID:MDC1 maintains genomic stability by participating in the amplification of ATM-dependent DNA damage signals. 1642 9

The protein kinase Chk2 (checkpoint kinase 2) is a major effector of the replication checkpoint. Chk2 activation is initiated by phosphorylation of Thr68, in the serine-glutamine/threonine-glutamine cluster domain (SCD), by ATM. The phosphorylated SCD-segment binds to the FHA domain of a second Chk2 molecule, promoting dimerisation of the protein and triggering phosphorylation of the activation segment/T-loop in the kinase domain. We have now determined the structure of the kinase domain of human Chk2 in complexes with ADP and a small-molecule inhibitor debromohymenialdisine. The structure reveals a remarkable dimeric arrangement in which T-loops are exchanged between protomers, to form an active kinase conformation in trans. Biochemical data suggest that this dimer is the biologically active state promoted by ATM-phosphorylation, and also suggests a mechanism for dimerisation-driven activation of Chk2 by trans-phosphorylation.
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PMID:Trans-activation of the DNA-damage signalling protein kinase Chk2 by T-loop exchange. 1679 75


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