Xrs2 Dependent and Independent Functions of the Mre11-Rad50 Complex

Oh, Julyun; Al-Zain, Amr; Cannavó, Elda; Ćejka, Petr; Symington, Lorraine S.

doi:10.1016/j.molcel.2016.09.011

Cited by 74 publications

(90 citation statements)

References 62 publications

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“…Sae2 physically interacts with MRX via Xrs2 and promotes MRX endonuclease action at blocked DNA ends (Cannavo and Cejka, 2014; Liang et al, 2015; Oh et al, 2016). We have found a physical interaction between CtIP and BLM and posit that this is important for BLM-mediated DNA unwinding.…”

Section: Discussionmentioning

confidence: 99%

Enhancement of BLM-DNA2-Mediated Long-Range DNA End Resection by CtIP

et al. 2017

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Summary DNA double-strand break repair by homologous recombination entails the resection of DNA ends to reveal ssDNA tails, which are used to invade a homologous DNA template. CtIP and its yeast ortholog Sae2 regulate the nuclease activity of MRE11 in the initial stage of resection. Deletion of CtIP in the mouse or SAE2 in yeast engenders a more severe phenotype than MRE11 nuclease inactivation, indicative of a broader role of CtIP/Sae2. Here, we provide biochemical evidence that CtIP promotes long-range resection via the BLM-DNA2 pathway. Specifically, CtIP interacts with BLM and enhances its helicase activity, and it also enhances DNA cleavage by DNA2. Thus, CtIP influences multiple aspects of end resection beyond MRE11 regulation.

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Section: Discussionmentioning

confidence: 99%

Enhancement of BLM-DNA2-Mediated Long-Range DNA End Resection by CtIP

et al. 2017

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“…These changes, which pull the linker to the Mre11 interface by ∼30 Å (19), are postulated to alter the Mre11 dimer symmetry thought to distinguish nuclease binding and activity for two-ended dsDNA breaks (symmetric dimer) and one-ended DNA forks (asymmetric dimer) (19). Overall, NBS1 (Xrs2 in S. cerevisiae ) acts a chaperone and adaptor coordinating interactions of the MR complex with other proteins (63, 64) and as a regulated activator of Mre11 nuclease (65). …”

Section: Mrn Complex: Structural Biochemistry and Biologymentioning

confidence: 99%

The MRE11–RAD50–NBS1 Complex Conducts the Orchestration of Damage Signaling and Outcomes to Stress in DNA Replication and Repair

Syed

Tainer

2018

Annu. Rev. Biochem.

336

345

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Genomic instability in disease and its fidelity in health depend on the DNA damage response (DDR), regulated in part from the complex of meiotic recombination 11 homolog 1 (MRE11), ATP-binding cassette–ATPase (RAD50), and phosphopeptide-binding Nijmegen breakage syndrome protein 1 (NBS1). The MRE11–RAD50–NBS1 (MRN) complex forms a multifunctional DDR machine. Within its network assemblies, MRN is the core conductor for the initial and sustained responses to DNA double-strand breaks, stalled replication forks, dysfunctional telomeres, and viral DNA infection. MRN can interfere with cancer therapy and is an attractive target for precision medicine. Its conformations change the paradigm whereby kinases initiate damage sensing. Delineated results reveal kinase activation, posttranslational targeting, functional scaffolding, conformations storing binding energy and en-abling access, interactions with hub proteins such as replication protein A (RPA), and distinct networks at DNA breaks and forks. MRN biochemistry provides prototypic insights into how it initiates, implements, and regulates multifunctional responses to genomic stress.

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“…For example, Mec1/Tel phosphorylation sites of Sae2 are not only required for nuclear localization of the repair complex, but are also critical for interactions with Xrs2, the S. cerevisiae Nbs1 homolog [102,103]. Furthermore phosphorylation of the human ortholog CtIP allows for binding both the FHA and BRCT domains of Nbs1 [61]; these interactions create the link between Ctp1/Sae2/CtIP and MRN, targeting the repair complex to DNA damage.…”

Section: Ctip Is a Regulatory Hub For Dsb Repair Pathway Choicementioning

confidence: 99%

CtIP/Ctp1/Sae2, molecular form fit for function

Andres¹,

Williams²

2017

DNA Repair

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Vertebrate CtIP, and its fission yeast (Ctp1), budding yeast (Sae2) and plant (Com1) orthologs have emerged as key regulatory molecules in cellular responses to DNA double strand breaks (DSBs). By modulating the nucleolytic 5′-3′ resection activity of the Mre11/Rad50/Nbs1 (MRN) DSB repair processing and signaling complex, CtIP/Ctp1/Sae2/Com1 is integral to the channeling of DNA double strand breaks through DSB repair by homologous recombination (HR). Nearly two decades since its discovery, emerging new data are defining the molecular underpinnings for CtIP DSB repair regulatory activities. CtIP homologs are largely intrinsically unstructured proteins comprised of expanded regions of low complexity sequence, rather than defined folded domains typical of DNA damage metabolizing enzymes and nucleases. A compact structurally conserved N-terminus forms a functionally critical tetrameric helical dimer of dimers (THDD) region that bridges CtIP oligomers, and is flexibly appended to a conserved C-terminal Sae2-homology DNA binding and DSB repair pathway choice regulatory hub which influences nucleolytic activities of the MRN core nuclease complex. The emerging evidence from structural, biophysical, and biological studies converges on CtIP having functional roles in DSB repair that include: 1) dynamic DNA strand coordination through direct DNA binding and DNA bridging activities, 2) MRN nuclease complex cofactor functions that direct MRN endonucleolytic cleavage of protein-blocked DSB ends and 3) acting as a protein binding hub targeted by the cell cycle regulatory apparatus, which influences CtIP expression and activity via layers of post-translational modifications, protein-protein interactions and DNA binding.

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Xrs2 Dependent and Independent Functions of the Mre11-Rad50 Complex

Cited by 74 publications

References 62 publications

Enhancement of BLM-DNA2-Mediated Long-Range DNA End Resection by CtIP

Enhancement of BLM-DNA2-Mediated Long-Range DNA End Resection by CtIP

The MRE11–RAD50–NBS1 Complex Conducts the Orchestration of Damage Signaling and Outcomes to Stress in DNA Replication and Repair

CtIP/Ctp1/Sae2, molecular form fit for function

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