Rad50 Adenylate Kinase Activity Regulates DNA Tethering by Mre11/Rad50 Complexes

Bhaskara, Venugopal; Dupré, Aude; Lengsfeld, Bettina Marie; Hopkins, Ben B.; Chan, Angela; Lee, Ji-Hoon; Zhang, Xiaoming; Gautier, Jean; Zakian, Virginia A.; Paull, Tanya T.

doi:10.1016/j.molcel.2007.01.028

Cited by 97 publications

(121 citation statements)

References 49 publications

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“…We also showed that the unwinding of DNA ends by the MRN complex is essential for the ATM stimulation. This was based on our analysis of the Rad50 S1202R mutant, which is deficient in ATP-dependent DNA unwinding (Moncalian et al, 2004) as well as in adenylate kinase activity (Bhaskara et al, 2007). In agreement with this finding, experiments using Xenopus egg extracts also showed that the wild-type MRN complex restores ATM kinase activity in Mre11-depleted Xenopus extracts but not the MR(S1202R)N-mutant complex (Costanzo et al, 2004).…”

Section: The Role Of the Mrn Complex In Atm Activationsupporting

confidence: 78%

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: The Role Of the Mrn Complex In Atm Activationsupporting

confidence: 78%

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

2007

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“…3d). We recently showed that Rad50-associated adenylate kinase activity is required for MRN-dependent DNA tethering 32 ; nevertheless, this activity was not inhibited by mirin ( Supplementary Fig. 5 online).…”

Section: Mirin Inhibits the Nuclease Activity Of Mre11mentioning

confidence: 95%

A forward chemical genetic screen reveals an inhibitor of the Mre11–Rad50–Nbs1 complex

et al. 2008

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The MRN (Mre11-Rad50-Nbs1)-ATM (ataxia-telangiectasia mutated) pathway is essential for sensing and signaling from DNA double-strand breaks. The MRN complex acts as a DNA damage sensor, maintains genome stability during DNA replication, promotes homology-dependent DNA repair and activates ATM. MRN is essential for cell viability, which has limited functional studies of the complex. Small-molecule inhibitors of MRN could circumvent this experimental limitation and could also be used as cellular radio-and chemosensitization compounds. Using cell-free systems that recapitulate faithfully the MRN-ATM signaling pathway, we designed a forward chemical genetic screen to identify inhibitors of the pathway, and we isolated Z-5-(4-hydroxybenzylidene)-2-imino-1,3-thiazolidin-4-one (mirin, 1) as an inhibitor of MRN. Mirin prevents MRN-dependent activation of ATM without affecting ATM protein kinase activity, and it inhibits Mre11-associated exonuclease activity. Consistent with its ability to target the MRN complex, mirin abolishes the G2/M checkpoint and homology-dependent repair in mammalian cells.The cellular response to DNA damage coordinates DNA repair with cell cycle progression and/or apoptosis. This response is essential to maintain the integrity of the genome. Defects in the DNA damage response can lead to genomic instability, a mutagenic condition leading to cancer predisposition 1,2 . Inherited mutations in the ATM, MRE11A and NBN genes are responsible for the cancer-prone syndromes ataxia-telangiectasia, ataxia telangiectasia-like disorder and Nijmegen breakage syndrome (NBS), respectively. These syndromes share clinical and cellular phenotypes including hypersensitivity to ionizing radiation (IR), radioresistant DNA synthesis, checkpoint deficiencies and chromosomal instability.

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“…Since meiotic DSB are formed in the chromatin loops rather than on the axial elements (Zickler & Kleckner 1999, Blat et al 2002, a role for Rad50 might be to bridge sister chromatids in order to establish a proper architecture of the sisters engaged in the pre-DSB complex (Wiltzius et al 2005). Finally, a recent study reported that a mutation affecting the adenylate kinase activity of Rad50, necessary for DNA tethering, also abolishes the formation of viable spores, but this study did not examine if meiotic DSB are formed or not (Bhaskara et al 2007). …”

Section: Roles Of the Mre11 Complex In Budding Yeast Meiosismentioning

confidence: 92%

“…Upon DNA binding via the globular domain, the intracomplex interaction is prevented and the intermolecular configuration is favoured, which allows DNA tethering (Moreno-Herrero et al 2005). In addition to ATP binding and hydrolysis, the conserved Fsignature motif_ in the C terminal ATPase domain of Rad50 bears an adenylate kinase activity, which is required for efficient tethering between different DNA molecules, independently of DNA binding (Bhaskara et al 2007). All these observations have led to the proposal that this molecular bridging by the Mre11 complex via the Rad50 coiled-coils constitutes the molecular basis of the Mre11 complex_s influence on recombinational DNA repair.…”

Section: Structure and Biochemical Properties Of The Mre11 Complexmentioning

confidence: 99%

The multiple roles of the Mre11 complex for meiotic recombination

2007

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During the first meiotic prophase, numerous DNA double-strand breaks (DSB) are formed in the genome in order to initiate recombination between homologous chromosomes. The conserved Mre11 complex, formed of Mre11, Rad50 and Nbs1 (Xrs2 in Saccharomyces cerevisiae) proteins, plays a crucial role in mitotic cells for sensing and repairing DSB. In meiosis the Mre11 complex is also required for meiotic recombination. Depending on the organisms, the Mre11 complex is required for the formation of the DSB catalysed by the transesterase Spo11 protein. It then plays a unique function in removing covalently attached Spo11 from the 5 ¶ extremity of the breaks through its nuclease activity, to allow further break resection. Finally, the Mre11 complex also plays a role during meiosis in bridging DNA molecules together and in sensing Spo11 DSB and activating the DNA damage checkpoint. In this article the different biochemical functions of the Mre11 complex required during meiosis are reviewed, as well as the consequences of Mre11 complex inactivation for meiosis in several organisms. Finally, I describe the meiotic phenotypes of several animal models that have been developed to model hypomorphic mutations of the Mre11 complex, involved in humans in some genetic instability disorders.

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Rad50 Adenylate Kinase Activity Regulates DNA Tethering by Mre11/Rad50 Complexes

Cited by 97 publications

References 49 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

A forward chemical genetic screen reveals an inhibitor of the Mre11–Rad50–Nbs1 complex

The multiple roles of the Mre11 complex for meiotic recombination

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