Independent Roles for Nibrin and Mre11-Rad50 in the Activation and Function of Atm

Cerosaletti, Karen; Concannon, Patrick

doi:10.1074/jbc.m404294200

Cited by 74 publications

(65 citation statements)

References 38 publications

(44 reference statements)

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“…ATM is the prototype signal transducer in the DNA damage response and hypomorphic mutations in Mre11 or Nbs1 result in disorders resembling ataxia-telangiectasia, suggesting that MRN and ATM function in similar pathways in vivo. Indeed, Nbs1 and Mre11 are required for the efficient autophosphorylation of ATM on serine 1981, the recruitment of activated ATM into irradiation-induced foci, and for the phosphorylation of downstream ATM targets (45)(46)(47)(48)(49)(50)(51). Interestingly, the reduction in CSR in Nbs1 ⌬/Ϫ B cells is of similar magnitude to that observed in ATM Ϫ/Ϫ mice (17, 41, 52).…”

Section: Colocalization Of Mre11 At the Igh Locus Depends On Aid In supporting

confidence: 56%

Genomic instability, endoreduplication, and diminished Ig class-switch recombination in B cells lacking Nbs1

Reina‐San‐Martin

Nussenzweig

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

128

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Mre11, Rad50, and Nbs1 form an evolutionarily conserved protein complex (Mre11-Rad50 -Nbs1, MRN) that has been proposed to function as a DNA damage sensor. Hypomorphic mutations in Mre11 and Nbs1 result in the human ataxia-telangiectasia-like disorder and Nijmegen breakage syndrome (NBS), respectively. In contrast, complete inactivation of Mre11, Rad50, or Nbs1 leads to early embryonic lethality, suggesting that the hypomorphic mutations may fail to reveal some of the essential functions of MRN. Here, we use Cre-loxP-mediated recombination to restrict Nbs1 deletion to B lymphocytes. We find that disruption of Nbs1 results in the accumulation of high levels of spontaneous DNA damage, impaired proliferation, and chromosomal endoreduplication. Moreover, we show that Ig class-switch recombination (CSR) is diminished in Nbs1-deficient B cells. The CSR defect is B cellintrinsic, independent of switch-region transcription, and a consequence of inefficient recombination at the DNA level. Our findings reveal that Nbs1 is critical for efficient Ig CSR and maintenance of the integrity of chromosomal structure and number.

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Section: Colocalization Of Mre11 At the Igh Locus Depends On Aid In supporting

confidence: 56%

Genomic instability, endoreduplication, and diminished Ig class-switch recombination in B cells lacking Nbs1

Reina‐San‐Martin

Nussenzweig

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

128

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“…The extent of reduction in activity was comparable in a moderate A-TLD patient, compound heterozygous for nonsense and missense mutations in Mre11, and was severely affected in a patient homozygous for a nonsense Mre11 mutation that markedly reduced the level of truncated Mre11 protein. Cerosaletti and Concannon (2004) showed that an Nbs1 construct (N6FR5), retaining the Mre11-binding site, gave rise to nuclear expression of Mre11/ Rad50 and stimulated ATM activation. This is also the case for the most common NBS mutation (657D5, 5 bp deletion giving rise to hypomorphic allele), which generates two fragments of the Nbs1 protein (Digweed et al, 1999).…”

Section: Atm Is Recruited To and Activated By The Mrn Complexmentioning

confidence: 99%

“…The N-terminal fragment contains the Mre11 binding site while the C-terminal fragment contains a conserved domain responsible for recruitment of ATM (Falck et al, 2005). Cerosaletti and Concannon (2004) showed that Mre11/Rad50 alone stimulated ATM activation after low doses of radiation. However, in these experiments, this complex was retained in the nucleus by an Nbs1 construct, NbFR5, that contained the N-terminal Mre11-binding site, but was lacking in the FHA and BRCT domains.…”

Section: Atm Is Recruited To and Activated By The Mrn Complexmentioning

confidence: 99%

ATM and the Mre11 complex combine to recognize and signal DNA double-strand breaks

2007

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The recognition and repair of DNA double-strand breaks (DSBs) is a complex process that draws upon a multitude of proteins. This is not surprising since this is a lethal lesion if left unrepaired and also contributes to genome instability and the consequential risk of cancer and other pathologies. Some of the key proteins that recognize these breaks in DNA are mutated in distinct genetic disorders that predispose to agent sensitivity, genome instability, cancer predisposition and/or neurodegeneration. These include members of the Mre11 complex (Mre11/Rad50/ Nbs1) and ataxia-telangiectasia (A-T) mutated (ATM), mutated in the human genetic disorder A-T. The mre11 (MRN) complex appears to be the major sensor of the breaks and subsequently recruits ATM where it is activated to phosphorylate in turn members of that complex and a variety of other proteins involved in cellcycle control and DNA repair. The MRN complex is also upstream of ATM and ATR (A-T-mutated and rad3-related) protein in responding to agents that block DNA replication. To date, more than 30 ATM-dependent substrates have been identified in multiple pathways that maintain genome stability and reduce the risk of disease. We focus here on the relationship between ATM and the MRN complex in recognizing and responding to DNA DSBs.

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“…40,41 Loss of the NBS1 FHA domain reduced the interaction between mutant NBS1 and MDC1 as well as the stable interaction between NBS1 and g-H2AX modified chromatin. 40 Although the NBS1 N-terminal region has been reported to be essential for functions including cell survival in response to IR, optimal ATM activation, for the intra-S phase checkpoint and efficient homologous recombination, 11,14,17,34,42 the direct phospho-interaction partner of the NBS1 FHA-BRCT domain remains unclear.…”

Section: Functional Domains Of Nbs1mentioning

confidence: 99%

“…[8][9][10][11] More recent studies indicated that NBS1 is not only a target of ATM-dependent phosphorylation but is required for the dissociation of inactive ATM dimers, for facilitating ATM accessibility to protein substrates, and for optimal IR-induced activation of ATM. [12][13][14][15][16][17][18][19][20] However, in NBS patient cells there is only a partial impairment in ATM activation. 17,18,21 Also, the phosphorylation of some ATM substrates is normal in NBS patient cells 9 and the extent of the checkpoint defect is less severe than in AT cells.…”

Section: Introductionmentioning

confidence: 99%

The NBS1-ATM Connection Revisited

Difilippantonio

Nussenzweig²

2007

Cell Cycle

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Nijmegen Breakage syndrome (NBS) is a rare autosomal recessive disorder characterized by microcephaly, immunodeficiency, and increased predisposition to the development of malignancy. 1,2 Due to the overlap of clinical and cellular features of patients with ataxia telangiectasia (AT), NBS was described as an AT variant syndrome until the underlying gene product mutation was identified. 3-5 Cells from both AT and NBS patients show increased sensitivity to ionizing radiation (IR), genomic instability and cell cycle checkpoint defects following DNA damage, 6,7 suggesting that both gene products participate in the same DNA damage response pathway. Here we highlight recent developments and refinements in our understanding of the interplay between NBS1 and ATM in vivo.

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Independent Roles for Nibrin and Mre11-Rad50 in the Activation and Function of Atm

Cited by 74 publications

References 38 publications

Genomic instability, endoreduplication, and diminished Ig class-switch recombination in B cells lacking Nbs1

Genomic instability, endoreduplication, and diminished Ig class-switch recombination in B cells lacking Nbs1

ATM and the Mre11 complex combine to recognize and signal DNA double-strand breaks

The NBS1-ATM Connection Revisited

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