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

Elisa Gobbini, Corinne Cassani, Jacopo Vertemara, Weibin Wang, Fabiana Mambretti, Erika Casari, Patrick Sung, Renata Tisi, Giuseppe Zampella, Maria Pia Longhese

Research output: Contribution to journalArticle

12 Scopus citations

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.

Original languageEnglish (US)
Article numbere98588
JournalEMBO Journal
Volume37
Issue number16
DOIs
StatePublished - Aug 15 2018
Externally publishedYes

Keywords

  • double-strand break
  • Exo1
  • MRX
  • resection
  • Sae2

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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