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RAD50, an SMC family member with multiple roles in DNA break repair: how does ATP affect function?

Kinoshita E, van der Linden E, Sanchez H, Wyman C - Chromosome Res. (2009)

Bottom Line: All current evidence indicates that ATP binding and hydrolysis cause architectural rearrangements in SMC protein complexes that are important for their functions in organizing DNA.In the case of the MRN complex, the functional significance of ATP binding and hydrolysis are not yet defined.We present some speculation on the role of ATP for function of the MRN complex based on the similarities and differences in the molecular architecture of the Rad50-containing complexes and the SMC complexes condensin and cohesin.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology and Genetics, Erasmus University Medical Center, Box 2040, 3000 CA Rotterdam, The Netherlands.

ABSTRACT
The protein complex including Mre11, Rad50, and Nbs1 (MRN) functions in DNA double-strand break repair to recognize and process DNA ends as well as signal for cell cycle arrest. Amino acid sequence similarity and overall architecture make Rad50 a member of the structural maintenance of chromosome (SMC) protein family. Like SMC proteins, Rad50 function depends on ATP binding and hydrolysis. All current evidence indicates that ATP binding and hydrolysis cause architectural rearrangements in SMC protein complexes that are important for their functions in organizing DNA. In the case of the MRN complex, the functional significance of ATP binding and hydrolysis are not yet defined. Here we review the data on the ATP-dependent activities of MRN and their possible mechanistic significance. We present some speculation on the role of ATP for function of the MRN complex based on the similarities and differences in the molecular architecture of the Rad50-containing complexes and the SMC complexes condensin and cohesin.

Show MeSH
ATP-induced domain dimerization and DNA binding for SMC and Rad50 complexes. Cohesin and condensin organize DNA by trapping duplexes within a protein ring. Interaction with DNA can be controlled by closing and opening the protein ring. Both ATP binding-induced dimerization of ATPase domains and interactions with partner proteins are involved. In some SMC examples there are specific DNA binding sites, for others DNA is topologically linked to the protein complex. Rad50 complexes do not form large coiled-coil bound protein rings when bound to DNA. The conformation induced by DNA binding presumably inhibits intra-complex interaction of the coiled-coil apexes. DNA can bind to and be enzymatically processed by Mre11. If DNA binds on the surface of Mre11 in the orientation shown, then ATP binding-induced association of the head domains would be expected to modulate access to the Mre11 DNA-binding site or stability of the Mre11–DNA interaction. Currently the orientation of the Mre11 DNA-binding surfaces and the Rad50 globular domains is not known; one of the possible arrangements is shown. Here intra-complex ATPase site dimerization is shown. Association of ATPase sites between different complexes is also possible. This inter-complex dimerization may be favored between complexes bound near each other on DNA. The position of Nbs1 and its influence on complex architecture have not yet been determined. This simplified illustration is based on current knowledge. More complexity will surely be introduced when Nbs1 can be placed in the complex and possible DNA-binding sites on Rad50 are taken into account
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Figure 5: ATP-induced domain dimerization and DNA binding for SMC and Rad50 complexes. Cohesin and condensin organize DNA by trapping duplexes within a protein ring. Interaction with DNA can be controlled by closing and opening the protein ring. Both ATP binding-induced dimerization of ATPase domains and interactions with partner proteins are involved. In some SMC examples there are specific DNA binding sites, for others DNA is topologically linked to the protein complex. Rad50 complexes do not form large coiled-coil bound protein rings when bound to DNA. The conformation induced by DNA binding presumably inhibits intra-complex interaction of the coiled-coil apexes. DNA can bind to and be enzymatically processed by Mre11. If DNA binds on the surface of Mre11 in the orientation shown, then ATP binding-induced association of the head domains would be expected to modulate access to the Mre11 DNA-binding site or stability of the Mre11–DNA interaction. Currently the orientation of the Mre11 DNA-binding surfaces and the Rad50 globular domains is not known; one of the possible arrangements is shown. Here intra-complex ATPase site dimerization is shown. Association of ATPase sites between different complexes is also possible. This inter-complex dimerization may be favored between complexes bound near each other on DNA. The position of Nbs1 and its influence on complex architecture have not yet been determined. This simplified illustration is based on current knowledge. More complexity will surely be introduced when Nbs1 can be placed in the complex and possible DNA-binding sites on Rad50 are taken into account

Mentions: The SMC cohesin and condensin complexes work in arranging DNA molecules by trapping one or more double helixes within a protein ring (Haering et al. 2002, 2008; Hirano 2005; Hirano and Hirano 2006) (Fig. 5). This arrangement does not require specific protein-DNA binding sites in order to work in organizing DNA molecules. Where specific binding sites have been identified or proposed they appear to be inside the potential protein ring. Thus, ring opening and closing via association of ATPase domains with each other or with partner proteins would control DNA access to these binding sites. By contrast, Rad50 complexes alone do not form stable rings via interactions at both ends of their coiled coils and are not expected to trap DNA within a large ring.


RAD50, an SMC family member with multiple roles in DNA break repair: how does ATP affect function?

Kinoshita E, van der Linden E, Sanchez H, Wyman C - Chromosome Res. (2009)

ATP-induced domain dimerization and DNA binding for SMC and Rad50 complexes. Cohesin and condensin organize DNA by trapping duplexes within a protein ring. Interaction with DNA can be controlled by closing and opening the protein ring. Both ATP binding-induced dimerization of ATPase domains and interactions with partner proteins are involved. In some SMC examples there are specific DNA binding sites, for others DNA is topologically linked to the protein complex. Rad50 complexes do not form large coiled-coil bound protein rings when bound to DNA. The conformation induced by DNA binding presumably inhibits intra-complex interaction of the coiled-coil apexes. DNA can bind to and be enzymatically processed by Mre11. If DNA binds on the surface of Mre11 in the orientation shown, then ATP binding-induced association of the head domains would be expected to modulate access to the Mre11 DNA-binding site or stability of the Mre11–DNA interaction. Currently the orientation of the Mre11 DNA-binding surfaces and the Rad50 globular domains is not known; one of the possible arrangements is shown. Here intra-complex ATPase site dimerization is shown. Association of ATPase sites between different complexes is also possible. This inter-complex dimerization may be favored between complexes bound near each other on DNA. The position of Nbs1 and its influence on complex architecture have not yet been determined. This simplified illustration is based on current knowledge. More complexity will surely be introduced when Nbs1 can be placed in the complex and possible DNA-binding sites on Rad50 are taken into account
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 5: ATP-induced domain dimerization and DNA binding for SMC and Rad50 complexes. Cohesin and condensin organize DNA by trapping duplexes within a protein ring. Interaction with DNA can be controlled by closing and opening the protein ring. Both ATP binding-induced dimerization of ATPase domains and interactions with partner proteins are involved. In some SMC examples there are specific DNA binding sites, for others DNA is topologically linked to the protein complex. Rad50 complexes do not form large coiled-coil bound protein rings when bound to DNA. The conformation induced by DNA binding presumably inhibits intra-complex interaction of the coiled-coil apexes. DNA can bind to and be enzymatically processed by Mre11. If DNA binds on the surface of Mre11 in the orientation shown, then ATP binding-induced association of the head domains would be expected to modulate access to the Mre11 DNA-binding site or stability of the Mre11–DNA interaction. Currently the orientation of the Mre11 DNA-binding surfaces and the Rad50 globular domains is not known; one of the possible arrangements is shown. Here intra-complex ATPase site dimerization is shown. Association of ATPase sites between different complexes is also possible. This inter-complex dimerization may be favored between complexes bound near each other on DNA. The position of Nbs1 and its influence on complex architecture have not yet been determined. This simplified illustration is based on current knowledge. More complexity will surely be introduced when Nbs1 can be placed in the complex and possible DNA-binding sites on Rad50 are taken into account
Mentions: The SMC cohesin and condensin complexes work in arranging DNA molecules by trapping one or more double helixes within a protein ring (Haering et al. 2002, 2008; Hirano 2005; Hirano and Hirano 2006) (Fig. 5). This arrangement does not require specific protein-DNA binding sites in order to work in organizing DNA molecules. Where specific binding sites have been identified or proposed they appear to be inside the potential protein ring. Thus, ring opening and closing via association of ATPase domains with each other or with partner proteins would control DNA access to these binding sites. By contrast, Rad50 complexes alone do not form stable rings via interactions at both ends of their coiled coils and are not expected to trap DNA within a large ring.

Bottom Line: All current evidence indicates that ATP binding and hydrolysis cause architectural rearrangements in SMC protein complexes that are important for their functions in organizing DNA.In the case of the MRN complex, the functional significance of ATP binding and hydrolysis are not yet defined.We present some speculation on the role of ATP for function of the MRN complex based on the similarities and differences in the molecular architecture of the Rad50-containing complexes and the SMC complexes condensin and cohesin.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology and Genetics, Erasmus University Medical Center, Box 2040, 3000 CA Rotterdam, The Netherlands.

ABSTRACT
The protein complex including Mre11, Rad50, and Nbs1 (MRN) functions in DNA double-strand break repair to recognize and process DNA ends as well as signal for cell cycle arrest. Amino acid sequence similarity and overall architecture make Rad50 a member of the structural maintenance of chromosome (SMC) protein family. Like SMC proteins, Rad50 function depends on ATP binding and hydrolysis. All current evidence indicates that ATP binding and hydrolysis cause architectural rearrangements in SMC protein complexes that are important for their functions in organizing DNA. In the case of the MRN complex, the functional significance of ATP binding and hydrolysis are not yet defined. Here we review the data on the ATP-dependent activities of MRN and their possible mechanistic significance. We present some speculation on the role of ATP for function of the MRN complex based on the similarities and differences in the molecular architecture of the Rad50-containing complexes and the SMC complexes condensin and cohesin.

Show MeSH