Homologous recombination is triggered by nucleolytic degradation (resection) of DNA double-strand breaks (DSBs). 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 DSBs and an enhanced DSB resection in G1, indicating that Exo1 has a direct function in preventing Ku association with DSBs. Molecular dynamics simulations show that rotation of the Mre11 capping domains is able to induce unwinding of double-strand DNA (dsDNA). The R10T substitution causes altered orientation of the Mre11 capping domain that leads to persistent melting of the dsDNA 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

Gobbini, E., Cassani, C., Vertemara, J., Wang, W., Mambretti, F., Casari, E., et al. (2018). The MRX complex regulates Exo1 resection activity by altering DNA end structure. EMBO JOURNAL, 37(16) [10.15252/embj.201798588].

The MRX complex regulates Exo1 resection activity by altering DNA end structure

Gobbini, Elisa
Primo
;
Cassani, Corinne;Vertemara, Jacopo;CASARI, ERIKA;Tisi, Renata;Zampella, Giuseppe;Longhese, Maria Pia
Ultimo
2018

Abstract

Homologous recombination is triggered by nucleolytic degradation (resection) of DNA double-strand breaks (DSBs). 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 DSBs and an enhanced DSB resection in G1, indicating that Exo1 has a direct function in preventing Ku association with DSBs. Molecular dynamics simulations show that rotation of the Mre11 capping domains is able to induce unwinding of double-strand DNA (dsDNA). The R10T substitution causes altered orientation of the Mre11 capping domain that leads to persistent melting of the dsDNA 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
Articolo in rivista - Articolo scientifico
MRX; Exo1; Sae2; double‐strand break; resection
English
2018
37
16
e98588
reserved
Gobbini, E., Cassani, C., Vertemara, J., Wang, W., Mambretti, F., Casari, E., et al. (2018). The MRX complex regulates Exo1 resection activity by altering DNA end structure. EMBO JOURNAL, 37(16) [10.15252/embj.201798588].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/201322
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