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The MRX complex regulates Exo1 resection activity by altering DNA end structure
Author(s) -
Gobbini Elisa,
Cassani Corinne,
Vertemara Jacopo,
Wang Weibin,
Mambretti Fabiana,
Casari Erika,
Sung Patrick,
Tisi Renata,
Zampella Giuseppe,
Longhese Maria Pia
Publication year - 2018
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201798588
Subject(s) - rad50 , nuclease , homologous recombination , biology , dna , dna damage , microbiology and biotechnology , dna repair , non homologous end joining , mutant , biophysics , dna binding protein , biochemistry , gene , transcription factor
Homologous recombination is triggered by nucleolytic degradation (resection) of DNA double‐strand breaks ( DSB s). DSB resection requires the Mre11‐Rad50‐Xrs2 ( MRX ) complex, which promotes the activity of Exo1 nuclease through a poorly understood mechanism. Here, we describe the Mre11‐R10T mutant variant that accelerates DSB resection compared to wild‐type Mre11 by potentiating Exo1‐mediated processing. This increased Exo1 resection activity leads to a decreased association of the Ku complex to DSB s and an enhanced DSB resection in G1, indicating that Exo1 has a direct function in preventing Ku association with DSB s. Molecular dynamics simulations show that rotation of the Mre11 capping domains is able to induce unwinding of double‐strand DNA (ds DNA ). The R10T substitution causes altered orientation of the Mre11 capping domain that leads to persistent melting of the ds DNA end. We propose that MRX creates a specific DNA end structure that promotes Exo1 resection activity by facilitating the persistence of this nuclease on the DSB ends, uncovering a novel MRX function in DSB resection.