MRE11 facilitates the removal of human topoisomerase II complexes from genomic DNA

Lee, Ka Cheong; Padget, Kay; Hannah, Curtis L.; Cowell, Ian G.; Moiani, Davide; Sońdka, Zbysław; Morris, Nicholas J.; Jackson, Graham; Cockell, Simon; Tainer, John A.; Austin, Caroline A.

doi:10.1242/bio.20121834

Cited by 62 publications

(54 citation statements)

References 56 publications

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“…In contrast, NBS1 inhibits the MR 3΄–5΄ exonuclease activity on clean DSB ends (72). The MRN complex can thus remove covalently linked topoisomerase complexes from genomic DNA in a mechanism requiring CtIP and BRCA1 (115, 118, 119). The MRN complex in association with CtIP also protects genomic loci at common fragile sites and palindromic repeats (120).…”

Section: Mrn and Double-strand Break Repairmentioning

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.

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323

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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Section: Mrn and Double-strand Break Repairmentioning

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.

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323

345

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“…It also initiates the activation of the DNA-damage response through ATM. Furthermore, Mre11 degrades stalled replication forks [11, 110] where it also removes covalently bound topoisomerase [111]. Finally, Mre11 promotes micro-homology end joining at breaks during transcription [112].…”

Section: Mre11mentioning

confidence: 99%

The cutting edges in DNA repair, licensing, and fidelity: DNA and RNA repair nucleases sculpt DNA to measure twice, cut once

Tsutakawa¹,

2014

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To avoid genome instability, DNA repair nucleases must precisely target the correct damaged substrate before they are licensed to incise. Damage identification is a challenge for all DNA damage response proteins, but especially for nucleases that cut the DNA and necessarily create a cleaved DNA repair intermediate, likely more toxic than the initial damage. How do these enzymes achieve exquisite specificity without specific sequence recognition or, in some cases, without a non-canonical DNA nucleotide? Combined structural, biochemical, and biological analyses of repair nucleases are revealing their molecular tools for damage verification and safeguarding against inadvertent incision. Surprisingly, these enzymes also often act on RNA, which deserves more attention. Here, we review protein-DNA structures for nucleases involved in replication, base excision repair, mismatch repair, double strand break repair (DSBR), and telomere maintenance: apurinic/apyrimidinic endonuclease 1 (APE1), Endonuclease IV (Nfo), tyrosyl DNA phosphodiesterase (TDP2), UV Damage endonuclease (UVDE), very short patch repair endonuclease (Vsr), Endonuclease V (Nfi), Flap endonuclease 1 (FEN1), exonuclease 1 (Exo1), RNase T and Meiotic recombination 11 (Mre11). DNA and RNA structure-sensing nucleases are essential to life with roles in DNA replication, repair, and transcription. Increasingly these enzymes are employed as advanced tools for synthetic biology and as targets for cancer prognosis and interventions. Currently their structural biology is most fully illuminated for DNA repair, which is also essential to life. How DNA repair enzymes maintain genome fidelity is one of the DNA double helix secrets missed by Watson-Crick, that is only now being illuminated though structural biology and mutational analyses. Structures reveal motifs for repair nucleases and mechanisms whereby these enzymes follow the old carpenter adage: measure twice, cut once. Furthermore, to measure twice these nucleases act as molecular level transformers that typically reshape the DNA and sometimes themselves to achieve extraordinary specificity and efficiency.

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“…Nes-cre mice (Lee et al 2012a;Aparicio et al 2016;Deshpande et al 2016;Hoa et al 2016). Importantly, no Top1cc accumulation was found in response to specific defects in the MRN complex, consistent with ATM regulation of Top1 likely being independent of the MRN complex (Katyal et al 2014).…”

Section: A-t and Atm: A Paradigm For Dna Damage-related Neurodegeneramentioning

confidence: 63%

Genome integrity and disease prevention in the nervous system

2017

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MRE11 facilitates the removal of human topoisomerase II complexes from genomic DNA

Cited by 62 publications

References 56 publications

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

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

The cutting edges in DNA repair, licensing, and fidelity: DNA and RNA repair nucleases sculpt DNA to measure twice, cut once

Genome integrity and disease prevention in the nervous system

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