4O43

DNA Double-Strand Break Repair Pathway Choice Is Directed by Distinct MRE11 Nuclease Activities

Summary for 4O43

• Entry DOI: 10.2210/pdb4o43/pdb
• Related: 4NZV 4O24 4O4K 4O5G
• Descriptor: Exonuclease, putative, MANGANESE (II) ION, (5~{E})-3-[(2~{R})-butan-2-yl]-5-[(4-hydroxyphenyl)methylidene]-2-sulfanylidene-1,3-thiazolidin-4-one, ... (4 entities in total)
• Functional Keywords: dna repair dna double-strand break repair thermophilic mre11 nuclease, dna repair dna double-strand break repair, dna binding protein-inhibitor complex, dna binding protein/inhibitor
• Biological source: Thermotoga maritima
• Total number of polymer chains: 2
• Total formula weight: 77956.99

Authors

Shibata, A.,Moiani, D.,Arvai, A.S.,Perry, J.,Harding, S.M.,Genois, M.,Maity, R.,Rossum-Fikkert, S.,Kertokalio, A.,Romoli, F.,Ismail, A.,Ismalaj, E.,Petricci, E.,Neale, M.J.,Bristow, R.G.,Masson, J.,Wyman, C.,Jeggo, P.A.,Tainer, J.A. (deposition date: 2013-12-18, release date: 2014-01-08, Last modification date: 2023-09-20)

Primary citation

Shibata, A.,Moiani, D.,Arvai, A.S.,Perry, J.,Harding, S.M.,Genois, M.M.,Maity, R.,van Rossum-Fikkert, S.,Kertokalio, A.,Romoli, F.,Ismail, A.,Ismalaj, E.,Petricci, E.,Neale, M.J.,Bristow, R.G.,Masson, J.Y.,Wyman, C.,Jeggo, P.A.,Tainer, J.A.
DNA Double-Strand Break Repair Pathway Choice Is Directed by Distinct MRE11 Nuclease Activities.
Mol.Cell, 53:7-18, 2014

PubMed Abstract: MRE11 within the MRE11-RAD50-NBS1 (MRN) complex acts in DNA double-strand break repair (DSBR), detection, and signaling; yet, how its endo- and exonuclease activities regulate DSBR by nonhomologous end-joining (NHEJ) versus homologous recombination (HR) remains enigmatic. Here, we employed structure-based design with a focused chemical library to discover specific MRE11 endo- or exonuclease inhibitors. With these inhibitors, we examined repair pathway choice at DSBs generated in G2 following radiation exposure. While nuclease inhibition impairs radiation-induced replication protein A (RPA) chromatin binding, suggesting diminished resection, the inhibitors surprisingly direct different repair outcomes. Endonuclease inhibition promotes NHEJ in lieu of HR, while exonuclease inhibition confers a repair defect. Collectively, the results describe nuclease-specific MRE11 inhibitors, define distinct nuclease roles in DSB repair, and support a mechanism whereby MRE11 endonuclease initiates resection, thereby licensing HR followed by MRE11 exonuclease and EXO1/BLM bidirectional resection toward and away from the DNA end, which commits to HR.

PubMed: 24316220
DOI: 10.1016/j.molcel.2013.11.003

Experimental method

X-RAY DIFFRACTION (2.4 Å)