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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.

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The multiple roles of Rad50 complexes in DNA break repair are illustrated. From top to bottom: Rad50 complexes bind to DNA early in the repair process to recognize double-strand breaks. Multiple Rad50 complexes bind to DNA. Rad50 complexes are involved in DNA processed including strand unwinding and nuclease digestion. This involves additional components that have not yet been clearly defined in all systems. DNA ends bound by Rad50 complex multimers are tethered by interaction among multiple coiled-coil apex hook domains. ATM is activated for cell-cycle signaling by interaction with DNA-bound Rad50 complexes; this step requires the Nbs1 component
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Figure 1: The multiple roles of Rad50 complexes in DNA break repair are illustrated. From top to bottom: Rad50 complexes bind to DNA early in the repair process to recognize double-strand breaks. Multiple Rad50 complexes bind to DNA. Rad50 complexes are involved in DNA processed including strand unwinding and nuclease digestion. This involves additional components that have not yet been clearly defined in all systems. DNA ends bound by Rad50 complex multimers are tethered by interaction among multiple coiled-coil apex hook domains. ATM is activated for cell-cycle signaling by interaction with DNA-bound Rad50 complexes; this step requires the Nbs1 component

Mentions: The MRN complex is involved at several distinct steps in DSB repair including break recognition, DNA end processing, and signaling for cell cycle arrest (Fig. 1). The MRN complex is a primary damage sensor involved in the early steps of DSB repair in both human and yeast cells (D’Amours and Jackson 2002). The importance of Rad50, Mre11, and Nbs1 genes in mammals is illustrated by the cell nonviability or embryonic lethality resulting when any of these three genes is disrupted (Xiao and Weaver 1997; Luo et al. 1999; Zhu et al. 2001). In humans, mutations in Nbs1 cause Nijmegen breakage syndrome (NBS). NBS patients show radiation sensitivity, immune system deficiency, and a high rate of malignancy (Shiloh 1997). NBS patients show phenotypes similar to ataxia-telangiectasia (A-T), a related radiation sensitivity disorder. A-T is caused by mutations in the A-T mutated gene (ATM), which encodes a large protein kinase that initiates DNA damage signaling in response to DSBs. A connection between MRN and ATM arose with the identification of two families with A-T-like disorder (ATLD), clinically identical to A-T but caused by mutations in Mre11 (Stewart et al. 1999).


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)

The multiple roles of Rad50 complexes in DNA break repair are illustrated. From top to bottom: Rad50 complexes bind to DNA early in the repair process to recognize double-strand breaks. Multiple Rad50 complexes bind to DNA. Rad50 complexes are involved in DNA processed including strand unwinding and nuclease digestion. This involves additional components that have not yet been clearly defined in all systems. DNA ends bound by Rad50 complex multimers are tethered by interaction among multiple coiled-coil apex hook domains. ATM is activated for cell-cycle signaling by interaction with DNA-bound Rad50 complexes; this step requires the Nbs1 component
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494100&req=5

Figure 1: The multiple roles of Rad50 complexes in DNA break repair are illustrated. From top to bottom: Rad50 complexes bind to DNA early in the repair process to recognize double-strand breaks. Multiple Rad50 complexes bind to DNA. Rad50 complexes are involved in DNA processed including strand unwinding and nuclease digestion. This involves additional components that have not yet been clearly defined in all systems. DNA ends bound by Rad50 complex multimers are tethered by interaction among multiple coiled-coil apex hook domains. ATM is activated for cell-cycle signaling by interaction with DNA-bound Rad50 complexes; this step requires the Nbs1 component
Mentions: The MRN complex is involved at several distinct steps in DSB repair including break recognition, DNA end processing, and signaling for cell cycle arrest (Fig. 1). The MRN complex is a primary damage sensor involved in the early steps of DSB repair in both human and yeast cells (D’Amours and Jackson 2002). The importance of Rad50, Mre11, and Nbs1 genes in mammals is illustrated by the cell nonviability or embryonic lethality resulting when any of these three genes is disrupted (Xiao and Weaver 1997; Luo et al. 1999; Zhu et al. 2001). In humans, mutations in Nbs1 cause Nijmegen breakage syndrome (NBS). NBS patients show radiation sensitivity, immune system deficiency, and a high rate of malignancy (Shiloh 1997). NBS patients show phenotypes similar to ataxia-telangiectasia (A-T), a related radiation sensitivity disorder. A-T is caused by mutations in the A-T mutated gene (ATM), which encodes a large protein kinase that initiates DNA damage signaling in response to DSBs. A connection between MRN and ATM arose with the identification of two families with A-T-like disorder (ATLD), clinically identical to A-T but caused by mutations in Mre11 (Stewart et al. 1999).

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