The Rad50 Signature Motif: Essential to ATP Binding and Biological Function

Moncalián, Gabriel; Lengsfeld, Bettina Marie; Bhaskara, Venugopal; Hopfner, Karl‐Peter; Karcher, Annette; Alden, Erinn; Tainer, John A.; Paull, Tanya T.

doi:10.1016/j.jmb.2003.11.026

Cited by 84 publications

(87 citation statements)

References 51 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: 80%

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: 80%

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

2007

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“…1G), ATP replaces ADP, and the endonucleolytic form of MRE11 is active again. Thus, opening and closing of RAD50-MRE11 are reminiscent of a DNA clamp, which characterizes other DNA binding members of the ABC-ATPase superfamily (40,53,54).…”

Section: Discussionmentioning

confidence: 99%

ATP Hydrolysis by RAD50 Protein Switches MRE11 Enzyme from Endonuclease to Exonuclease

Majka

Alford

Ausió

et al. 2012

Journal of Biological Chemistry

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Background: RAD50-MRE11-Nbs1 complex is essential for DNA repair. Results: ATP binding by RAD50 closes the complex; MRE11 is an endonuclease. ATP hydrolysis opens the complex; MRE11 is an exonuclease. Conclusion: ATP hydrolysis is a switch converting MRE11 from an endonuclease to an exonuclease. Significance: ATP-dependent nuclease switch provides a mechanism of how RAD50-MRE11 complex is able to coordinate DNA repair.

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“…Rad50 unwinds the DNA ends (36), enabling the recruitment of cellular nucleases such as Exo1 and Sae2, which play a role in resecting the broken ends (35). The 3Ј-single-stranded tail arising after resection serves as a substrate for the sequential recruitment RPA and Brca2, ultimately resulting in the formation of Rad51 nucleofilaments on the 3Ј-single-stranded tails.…”

Section: Discussionmentioning

confidence: 99%

Physical Interaction between the Herpes Simplex Virus Type 1 Exonuclease, UL12, and the DNA Double-Strand Break-Sensing MRN Complex

Balasubramanian

Bai

Buchek

et al. 2010

J Virol

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The herpes simplex virus type 1 (HSV-1) alkaline nuclease, encoded by the UL12 gene, plays an important role in HSV-1 replication, as a UL12 null mutant displays a severe growth defect. The HSV-1 alkaline exonuclease UL12 interacts with the viral single-stranded DNA binding protein ICP8 and promotes strand exchange in vitro in conjunction with ICP8. We proposed that UL12 and ICP8 form a two-subunit recombinase reminiscent of the phage lambda Red ␣/␤ recombination system and that the viral and cellular recombinases contribute to viral genome replication through a homologous recombination-dependent DNA replication mechanism. To test this hypothesis, we identified cellular interaction partners of UL12 by using coimmunoprecipitation. We report for the first time a specific interaction between UL12 and components of the cellular MRN complex, an important factor in the ATM-mediated homologous recombination repair (HRR) pathway. This interaction is detected early during infection and does not require viral DNA or other viral or cellular proteins. The region of UL12 responsible for the interaction has been mapped to the first 125 residues, and coimmunoprecipitation can be abolished by deletion of residues 100 to 126. These observations support the hypothesis that cellular and viral recombination factors work together to promote efficient HSV-1 growth.The herpes simplex virus (HSV) genome replicates in the nucleus of an infected host cell, resulting in the production of longer-than-unit-length head-to-tail concatemers of viral DNA. Production of infectious virus requires the processing of concatemeric DNA into unit-length genomes by the packaging machinery followed by encapsidation into preassembled capsids (63). Several lines of evidence suggest that recombination plays a role in concatemer formation (69). Genomic inversions, proposed to occur through recombination, can be detected very early during infection, and these inversions require sequence homology (2,23,56). In addition, replication intermediates in HSV type 1 (HSV-1)-infected cells adopt a complex nonlinear structure that does not migrate in a pulsed-field gel, even after digestion with an enzyme that cuts once per unit length of the genome (1,33,51,71). Electron micrographs have revealed that replication intermediates are branched and contain Y-and X-shaped junctions (19,52). Furthermore, high levels of recombination have been reported not only between coinfecting viral strains (4, 17, 50, 62, 66) but also in plasmids containing repeated sequence elements (10, 11). These observations, taken together, are not consistent with a simple rolling circle mechanism of replication and suggest that, reminiscent of the bacteriophages T4 and lambda, HSV-1 utilizes a recombination-dependent replication mechanism to generate concatemeric viral DNA.We have previously reported that virus-encoded proteins are capable of participating in recombination events in vitro. The viral 5Ј-3Ј alkaline exonuclease (UL12) and the single-strand binding protein (ICP8) together mediate stra...

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The Rad50 Signature Motif: Essential to ATP Binding and Biological Function

Cited by 84 publications

References 51 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

ATP Hydrolysis by RAD50 Protein Switches MRE11 Enzyme from Endonuclease to Exonuclease

Physical Interaction between the Herpes Simplex Virus Type 1 Exonuclease, UL12, and the DNA Double-Strand Break-Sensing MRN Complex

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