ATM phosphorylates p95/nbs1 in an S-phase checkpoint pathway

Lim, Dae‐Sik; Kim, Seong-Tae; Xu, Bo; Maser, Richard S.; Lin, J. G.; Petrini, John H.J.; Kastan, Michael B.

doi:10.1038/35007091

Cited by 716 publications

(536 citation statements)

References 24 publications

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“…Several studies showed that the expression of S343A mutant Nbs1 in NBS cells resulted in partial defects in IR-induced S-phase checkpoint activation, radiosensitivity and partial defects in ATM-dependent phosphorylation events including Chk2, SMC1 and FANCD2 (Lim et al, 2000;Buscemi et al, 2001;Nakanishi et al, 2002;Yazdi et al, 2002). Our studies also showed that the MRN complex containing mutant Nbs1 (S343A) failed to stimulate the phosphorylation of Chk2 by ATM although p53 phosphorylation was normal in vitro.…”

Section: Phosphorylation Of Nbs1supporting

confidence: 50%

“…The Mre11/Rad50/Nbs1 (MRN) complex has been shown by several groups to be required for the ATM signaling pathway (Lim et al, 2000;Buscemi et al, 2001;Girard et al, 2002;Nakanishi et al, 2002;Yazdi et al, 2002;Uziel et al, 2003). Most of these studies were performed using cells derived from patients with Nijmegen Breakage Syndrome (NBS) or Ataxia-TelangiectasiaLike-Disorder (ATLD), which are caused by hypomorphic alleles of the Nbs1 or Mre11 genes, respectively (Carney et al, 1998;Varon et al, 1998;Stewart et al, 1999).…”

Section: The Role Of the Mrn Complex In Atm Activationmentioning

confidence: 99%

“…(b) Nbs1 is a 90 kDa protein, consisting of 754 amino acids. The phosphorylation sites (P) show the serine residues that are phosphorylated by ATM (Gatei et al, 2000;Lim et al, 2000;Stewart et al, 2001;Kim et al, 2002;Lee et al, 2003b). The domains within Nbs1 include the forkhead-associated (FHA) domain (Featherstone and Jackson, 1998), the breast cancer C-terminal (BRCT) domains (Becker et al, 2006), the Mre11-binding domain (MBD) (Desai-Mehta et al, 2001) and the ATM-interacting domain (Falck et al, 2005).…”

Section: Role Of the C-terminus Of Nbs1mentioning

confidence: 99%

“…Nbs1 is phosphorylated in an ATM-dependent manner after DNA damage on residues Ser278, Ser343 and Ser615 (Gatei et al, 2000;Lim et al, 2000;Stewart et al, 2001;Kim et al, 2002;Lee et al, 2003b). Several studies showed that the expression of S343A mutant Nbs1 in NBS cells resulted in partial defects in IR-induced S-phase checkpoint activation, radiosensitivity and partial defects in ATM-dependent phosphorylation events including Chk2, SMC1 and FANCD2 (Lim et al, 2000;Buscemi et al, 2001;Nakanishi et al, 2002;Yazdi et al, 2002).…”

Section: Phosphorylation Of Nbs1mentioning

confidence: 99%

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Activation and regulation of ATM kinase activity in response to DNA double-strand breaks

2007

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The ataxia-telangiectasia-mutated (ATM) protein kinase is rapidly and specifically activated in response to DNA double-strand breaks in eukaryotic cells. In this review, we summarize recent insights into the mechanism of ATM activation, focusing on the role of the Mre11/Rad50/Nbs1 (MRN) complex in this process. We also compare observations of the ATM activation process in different biological systems and highlight potential candidates for cellular factors that may participate in regulating ATM activity in human cells.

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Section: Phosphorylation Of Nbs1supporting

confidence: 50%

Section: The Role Of the Mrn Complex In Atm Activationmentioning

confidence: 99%

Section: Role Of the C-terminus Of Nbs1mentioning

confidence: 99%

Section: Phosphorylation Of Nbs1mentioning

confidence: 99%

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Activation and regulation of ATM kinase activity in response to DNA double-strand breaks

2007

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“…Once activated it then phosphorylates a series of substrates including Nbs1. Specific phosphorylation of Nbs1 on S287 and S343 plays a role in the activation of the intra-S-phase checkpoint (Lim et al, 2000). Yazdi et al (2002) showed that ATMdependent phosphorylation of Nbs1 was required for phosphorylation of SMC1, implying that Nbs1, presumably as part of the MRN complex, was an adaptor in an ATM/Nbs1/SMC1 pathway controlling the S-phase checkpoint.…”

Section: Perspectivementioning

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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Cell Cycle Genes: pRb and p53

Sang

Giordano

2003

When Cells Die II

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Cell division is the process by which two daughter cells are reproduced from a single cell. Two types of division may occur: mitosis and meiosis. Meiosis produces germ cells with a haploid set of chromosomes by one round of DNA replication and two rounds of cell division. Mitosis, however, takes place in somatic cells and generates two diploid daughter cells that are identical to the original cell. The orchestrated sequence of cellular processes by which one mother cell grows and divides into two daughter cells is termed cell division cycle, or cell cycle. In multicellular organisms, a precisely regulated balance between cell division and cell death is essential for normal development and homeostasis.A typical cell cycle consists of four phases: a G1 phase, which is the first gap; an S phase, in which DNA synthesis takes place; a G2 phase or second gap; and an M phase, otherwise known as the mitotic phase. The G1-S-G2 phases are collectively termed interphase. Based on morphological changes, the mitotic phase can be further divided into prophase (DNA condensed to form sister chromatids), metaphase (sister chromatids migrate to the equatorial plane of the cell and are oriented in the center of the mitotic spindle), anaphase (simultaneous separation of all the sister chromatids at their centromeres), and telophase (chromosomes uncoil and new nuclear membranes When Cells Die II, Edited

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ATM phosphorylates p95/nbs1 in an S-phase checkpoint pathway

Cited by 716 publications

References 24 publications

Activation and regulation of ATM kinase activity in response to DNA double-strand breaks

Activation and regulation of ATM kinase activity in response to DNA double-strand breaks

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

Cell Cycle Genes: pRb and p53

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