Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P16104 (H2AX)
 3,930 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

MRE11, RAD50 and NBS1 form a highly conserved protein complex (the MRE11 complex) that is involved in the detection, signalling and repair of DNA damage. We identify MDC1 (KIAA0170/NFBD1), a protein that contains a forkhead-associated (FHA) domain and two BRCA1 carboxy-terminal (BRCT) domains, as a binding partner for the MRE11 complex. We show that, in response to ionizing radiation, MDC1 is hyperphosphorylated in an ATM-dependent manner, and rapidly relocalizes to nuclear foci that also contain the MRE11 complex, phosphorylated histone H2AX and 53BP1. Downregulation of MDC1 expression by small interfering RNA yields a radio-resistant DNA synthesis (RDS) phenotype and prevents ionizing radiation-induced focus formation by the MRE11 complex. However, downregulation of MDC1 does not abolish the ionizing radiation-induced phosphorylation of NBS1, CHK2 and SMC1, or the degradation of CDC25A. Furthermore, we show that overexpression of the MDC1 FHA domain interferes with focus formation by MDC1 itself and by the MRE11 complex, and induces an RDS phenotype. These findings reveal that MDC1-mediated focus formation by the MRE11 complex at sites of DNA damage is crucial for the efficient activation of the intra-S-phase checkpoint.
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PMID:MDC1 is required for the intra-S-phase DNA damage checkpoint. 1260 3

The induction of DNA double-strand breaks (DSBs) by ionizing radiation in mammalian chromosomes leads to the phosphorylation of Ser-139 in the replacement histone H2AX, but the molecular mechanism(s) of the elimination of phosphorylated H2AX (called gamma-H2AX) from chromatin in the course of DSB repair remains unknown. We showed earlier that gamma-H2AX cannot be replaced by exchange with free H2AX, suggesting the direct dephosphorylation of H2AX in chromatin by a protein phosphatase. Here we studied the dynamics of dephosphorylation of gamma-H2AX in vivo and found that more than 50% was dephosphorylated in 3 h, but a significant amount of gamma-H2AX could be detected even 6 h after the induction of DSBs. At this time, a significant fraction of the gamma-H2AX nuclear foci co-localized with the foci of RAD50 protein that did not co-localize with replication sites. However, gamma-H2AX could be detected in some cells treated with methyl methanesulfonate which accumulated RAD18 protein at stalled replication sites. We also found that calyculin A inhibited early elimination of gamma-H2AX and DSB rejoining in vivo and that protein phosphatase 1 was able to remove phosphate groups from gamma-H2AX-containing chromatin in vitro. Our results confirm the tight association between DSBs and gamma-H2AX and the coupling of its in situ dephosphorylation to DSB repair.
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PMID:Dephosphorylation of histone gamma-H2AX during repair of DNA double-strand breaks in mammalian cells and its inhibition by calyculin A. 1292 89

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

NBS1 is the key regulator of the RAD50/MRE11/NBS1 (R/M/N) protein complex, a sensor and mediator for cellular DNA damage response. NBS1 potentiates the enzymatic activity of MRE11 and directs the R/M/N complex to sites of DNA damage, where it forms nuclear foci by interacting with phosphorylated H2AX. The R/M/N complex also activates the ATM kinase, which is a major kinase involved in the activation of DNA damage signal pathways. The ATM requires the R/M/N complex for its own activation following DNA damage, and for conformational change to develop a high affinity for target proteins. In addition, association of NBS1 with PML, the promyelocytic leukemia protein, is required to form nuclear bodies, which have various functions depending on their location and composition. These nuclear bodies function not only in response to DNA damage, but are also involved in telomere maintenance when they are located on telomeres. In this review, we describe the role of NBS1 in the maintenance of genetic stability through the activation of cell-cycle checkpoints, DNA repair, and protein relocation.
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PMID:The Nijmegen breakage syndrome gene and its role in genome stability. 1525 9

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

The cellular response to DNA damage includes the orderly recruitment of many protein complexes to DNA lesions. The MRE11-RAD50-NBS1 (MRN) complex is well known to localize early to sites of DNA damage, but the post-translational modifications required to mobilize it to DNA damage sites are poorly understood. Recently, we have shown that MRE11 is arginine methylated in a C-terminal glycine-arginine rich (GAR) domain by protein arginine methyltransferase 1 (PRMT1). Arginine methylation is required for the exonuclease activity of MRE11 and the intra-S phase DNA damage response. Herein, we report that cells treated with methylase inhibitors failed to relocalize MRE11 from PML nuclear bodies to sites of DNA damage and formed few gamma-H2AX foci. We also demonstrate that PRMT1 is a component of PML nuclear bodies where it colocalizes with MRE11.Using cellular fractionation, we demonstrate that methylated MRE11 is predominantly associated with nuclear structures and that MRE11 methylated arginines were required for this association. These results suggest that MRE11 methylation regulates its association with nuclear structures such as PML nuclear bodies and sites of DNA damage.
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PMID:Methylation of MRE11 regulates its nuclear compartmentalization. 1597 Jun 67

Hypomorphic mutations which lead to decreased function of the NBS1 gene are responsible for Nijmegen breakage syndrome, a rare autosomal recessive hereditary disorder that imparts an increased predisposition to development of malignancy. The NBS1 protein is a component of the MRE11/RAD50/NBS1 complex that plays a critical role in cellular responses to DNA damage and the maintenance of chromosomal integrity. Using small interfering RNA transfection, we have knocked down NBS1 protein levels and analyzed relevant phenotypes in two closely related human lymphoblastoid cell lines with different p53 status, namely wild-type TK6 and mutated WTK1. Both TK6 and WTK1 cells showed an increased level of ionizing radiation-induced mutation at the TK and HPRT loci, impaired phosphorylation of H2AX (gamma-H2AX), and impaired activation of the cell cycle checkpoint regulating kinase, Chk2. In TK6 cells, ionizing radiation-induced accumulation of p53/p21 and apoptosis were reduced. There was a differential response to ionizing radiation-induced cell killing between TK6 and WTK1 cells after NBS1 knockdown; TK6 cells were more resistant to killing, whereas WTK1 cells were more sensitive. NBS1 deficiency also resulted in a significant increase in telomere association that was independent of radiation exposure and p53 status. Our results provide the first experimental evidence that NBS1 deficiency in human cells leads to hypermutability and telomere associations, phenotypes that may contribute to the cancer predisposition seen among patients with this disease.
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PMID:NBS1 knockdown by small interfering RNA increases ionizing radiation mutagenesis and telomere association in human cells. 1599 26

Exposure to ionizing radiation (IR) results in the formation of DNA double strand breaks, resulting in the activation of phosphatidylinositol 3'-kinase-like kinases ATM, ATR and DNK-PKcs. A physiologically important downstream target is the minor histone H2A variant, H2AX, which is rapidly phosphorylated on Ser 139 of the carboxyl tail after IR. Recent work suggests that phosphorylated H2AX (gamma-H2AX) plays an important role in the recruitment and/or retention of DNA repair and checkpoint proteins such as BRCA1, MRE11/RAD50/NBS1 complex, MDC1 and 53BP1. H2AX-/- mouse embryonic fibroblasts are radiation sensitive and demonstrate deficits in repairing DNA damage compared to their wildtype counterparts. Cells treated with peptide inhibitors of gamma-H2AX demonstrate increased radiosensitivity following radiation compared with untreated irradiated cells. Analysis of the kinetics of gamma-H2AX clearance after IR or other DNA damaging agents reveals a correlation between increased gamma-H2AX persistence and unrepaired DNA damage and cell death. These data highlight the potential of post-translational modifications of chromatin as a therapeutic target for enhancing the efficacy of radiotherapy. Therapies that either block gamma-H2AX foci formation by inhibiting upstream kinase activity or that directly inhibit H2AX function may interfere with DNA damage repair processes and warrant further investigation as potential radiosensitizing agents. Agents that increase persistence of gamma-H2AX after IR are likely to increase unrepaired DNA damage.
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PMID:gamma-H2AX as a therapeutic target for improving the efficacy of radiation therapy. 1671 57


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