The Rad50 hook domain regulates DNA damage signaling and tumorigenesis Journal Article

   


Authors: Roset, R.; Inagaki, A.; Hohl, M.; Brenet, F.; Lafrance-Vanasse, J.; Lange, J.; Scandura, J. M.; Tainer, J. A.; Keeney, S.; Petrini, J. H. J.
Article Title: The Rad50 hook domain regulates DNA damage signaling and tumorigenesis
Abstract: The Mre11 complex (Mre11, Rad50, and Nbs1) is a central component of the DNA damage response (DDR), governing both double-strand break repair and DDR signaling. Rad50 contains a highly conserved Zn2+-dependent homodimerization interface, the Rad50 hook domain. Mutations that inactivate the hook domain produce a null phenotype. In this study, we analyzed mutants with reduced hook domain function in an effort to stratify hookdependent Mre11 complex functions. One of these alleles, Rad5046, conferred reduced Zn2+ affinity and dimerization efficiency. Homozygous Rad5046/46 mutations were lethal in mice. However, in the presence of wildtype Rad50, Rad5046 exerted a dominant gain-of-function phenotype associated with chronic DDR signaling. At the organismal level, Rad50+/46 exhibited hydrocephalus, liver tumorigenesis, and defects in primitive hematopoietic and gametogenic cells. These outcomes were dependent on ATM, as all phenotypes were mitigated in Rad50+/46 Atm+/- mice. These data reveal that the murine Rad50 hook domain strongly influences Mre11 complex-dependent DDR signaling, tissue homeostasis, and tumorigenesis. © 2014 Roset et al.
Keywords: signal transduction; controlled study; nonhuman; protein domain; protein function; mouse; phenotype; mre11 protein; rad50 protein; allele; dna damage; rad50; dna repair; germ cell; animal experiment; heterozygote; stem cell; hematopoietic cell; atm protein; dimerization; homeostasis; double-strand breaks; hydrocephalus; atm; mre11 complex; dna damage checkpoint; zinc ion; liver carcinogenesis; priority journal; article
Journal Title: Genes and Development
Volume: 28
Issue: 5
ISSN: 0890-9369
Publisher: Cold Spring Harbor Laboratory Press  
Date Published: 2014-03-01
Start Page: 451
End Page: 462
Language: English
DOI: 10.1101/gad.236745.113
PROVIDER: scopus
PMCID: PMC3950343
PUBMED: 24532689
DOI/URL:

http://www.scopus.com/inward/record.url?eid=2-s2.0-84896820650&partnerID=40&md5=09cbc7bca545bcfb92663bad24885af8
Notes: Export Date: 1 May 2014 -- CODEN: GEDEE -- Source: Scopus
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MSK Authors
  1. Scott N Keeney
    138 Keeney
  2. Julian Lange
    18 Lange
  3. Ramon Roset Huguet
    2 Roset Huguet
  4. John Petrini
    94 Petrini
  5. Marcel Hohl
    13 Hohl
  6. Akiko Inagaki
    9 Inagaki
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