<scp>ATP</scp>‐dependent <scp>DNA</scp> binding, unwinding, and resection by the Mre11/Rad50 complex

Liu, Yaqi; Sung, Sihyun; Kim, Youngran; Li, Fuyang; Gwon, Gwanghyun; Jo, Aera; Kim, Ae Kyoung; Kim, Taeyoon; Song, Ok Kyu; Lee, Sang Eun; Cho, Yunje

doi:10.15252/embj.201592462

Cited by 106 publications

(134 citation statements)

References 66 publications

Supporting

Mentioning

126

Contrasting

Order By: Relevance

“…MRE11 key features are an N-terminal core nuclease domain followed by a cap domain that restricts access to the nuclease active site and a flexibly linked RAD50 binding motif (21, 22, 36–39). X-ray structures of P. furiosus Mre11 revealed the two-domain architecture for the catalytic core (40).…”

Section: Mrn Complex: Structural Biochemistry and Biologymentioning

confidence: 99%

“…In the ATP-free or hydrolyzed state seen in the Thermotoga maritima MR complex,the Rad50 ATPase subunits are flexible and relatively open with the arms relaxed (51, 52) ( Figure 2 b ). In contrast, upon ATP binding, Rad50 closes into a single, more rigid conformation in which both head domains (N- and C-terminal) are interacting with each other in trans and form a central groove that can accommodate double-stranded DNA (dsDNA) ( Figure 2 a ) (21, 38, 51). Notably, an added DNA binding site at the coiled-coil domain on Rad50 subunits is seen for the complex of Rad50 (nucleotide binding domain) and Mre11 (helix-loop-helix domain) with AMPPNP and dsDNA (53).…”

Section: Mrn Complex: Structural Biochemistry and Biologymentioning

confidence: 99%

“…Importantly, the closed-state (ATP-bound) Rad50 renders dsDNA inaccessible to the Mre11 nuclease active site ( Figure 2 a ) (21). However, ATP hydrolysis opens dsDNA so that flexible ssDNA may access the Mre11 active site (21).…”

Section: Mrn Complex: Structural Biochemistry and Biologymentioning

confidence: 99%

“…However, ATP hydrolysis opens dsDNA so that flexible ssDNA may access the Mre11 active site (21). In another ATPase machine, FlaI (58), a structurally defined intermediate with bound phosphate ion (PO 4 3– ) released from ADP partially opens subunit contacts: This structure suggests that RAD50 conformational intermediates may allow MRE11 ssDNA endonuclease activity while restricting dsDNA and MRE11 exonuclease excision.…”

Section: Mrn Complex: Structural Biochemistry and Biologymentioning

confidence: 99%

“…NBS1 interacts with ATM kinase plus its N-terminal phosphopeptide-interacting domains that link MRN to other partners including the C-terminal binding protein (CtBP)-interacting protein (CtIP) (19, 20). As it directly binds NBS1, DNA, and RAD50, the MRE11 nuclease dimer is the core of the MRN complex (21–23). We therefore update the two-step MRE11 nuclease incision model to explain its endo- and exonuclease properties in light of recent structures, including the eukaryotic RAD50 Zn-hook and CtIP N-terminal domain.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

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

View full text Add to dashboard Cite

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.

show abstract

Section: Mrn Complex: Structural Biochemistry and Biologymentioning

confidence: 99%

Section: Mrn Complex: Structural Biochemistry and Biologymentioning

confidence: 99%

Section: Mrn Complex: Structural Biochemistry and Biologymentioning

confidence: 99%

Section: Mrn Complex: Structural Biochemistry and Biologymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

View full text Add to dashboard Cite

show abstract

Invited review: Architectures and mechanisms of ATP binding cassette proteins

Hopfner

2016

Biopolymers

View full text Add to dashboard Cite

ATP binding cassette (ABC) ATPases form chemo-mechanical engines and switches that function in a broad range of biological processes. Most prominently, a very large family of integral membrane NTPases -ABC transporters -catalyzes the import or of a diverse molecules across membranes. ABC proteins are also critical components of the chromosome segregation, recombination and DNA repair machineries and regulate or catalyze critical steps of ribosomal protein synthesis. Recent structural and mechanistic studies draw interesting architectural and mechanistic parallels between diverse ABC proteins. Here I review the current state of our understanding how NTP-dependent conformational changes of ABC proteins drive diverse biological processes.

show abstract

Structural basis of homologous recombination

Sun

McCorvie

Yates

et al. 2019

Cell. Mol. Life Sci.

107

View full text Add to dashboard Cite

Homologous recombination (HR) is a pathway to faithfully repair DNA double-strand breaks (DSBs). At the core of this pathway is a DNA recombinase, which, as a nucleoprotein filament on ssDNA, pairs with homologous DNA as a template to repair the damaged site. In eukaryotes Rad51 is the recombinase capable of carrying out essential steps including strand invasion, homology search on the sister chromatid and strand exchange. Importantly, a tightly regulated process involving many protein factors has evolved to ensure proper localisation of this DNA repair machinery and its correct timing within the cell cycle. Dysregulation of any of the proteins involved can result in unchecked DNA damage, leading to uncontrolled cell division and cancer. Indeed, many are tumour suppressors and are key targets in the development of new cancer therapies. Over the past 40 years, our structural and mechanistic understanding of homologous recombination has steadily increased with notable recent advancements due to the advances in single particle cryo electron microscopy. These have resulted in higher resolution structural models of the signalling proteins ATM (ataxia telangiectasia mutated), and ATR (ataxia telangiectasia and Rad3-related protein), along with various structures of Rad51. However, structural information of the other major players involved, such as BRCA1 (breast cancer type 1 susceptibility protein) and BRCA2 (breast cancer type 2 susceptibility protein), has been limited to crystal structures of isolated domains and low-resolution electron microscopy reconstructions of the full-length proteins. Here we summarise the current structural understanding of homologous recombination, focusing on key proteins in recruitment and signalling events as well as the mediators for the Rad51 recombinase. Keywords Homologous recombination • Cryo electron microscopy • X-ray crystallography • Double-strand break repair • DNA damage signalling and repair Abbreviations ADP Adenosine diphosphate AMP-PNP Adenylyl-imidodiphosphate ATM Ataxia telangiectasia mutated ATP Adenosine triphosphate ATR Ataxia telangiectasia and Rad3-related protein BARD1 BRCA1-associated RING domain protein 1 BRCA1 Breast cancer type 1 susceptibility protein BRCA2 Breast cancer type 2 susceptibility protein BRCT BRCA1 C-terminal domain cryoEM Cryo electron microscopy DDR DNA damage response DSB Double-strand break EJ End joining MRE11 Meiotic recombination 11 homolog 1 MRN MRE11 RAD50 NBS1 NBS1 Nijmegen breakage syndrome protein 1 OB Oligonucleotide/oligosaccharide-binding PALB2 Partner and localiser of BRCA2 RPA Replication protein A

show abstract

ATP‐dependent DNA binding, unwinding, and resection by the Mre11/Rad50 complex

Cited by 106 publications

References 66 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

Invited review: Architectures and mechanisms of ATP binding cassette proteins

Structural basis of homologous recombination

Contact Info

Product

Resources

About