| First Author | Roset R | Year | 2014 |
| Journal | Genes Dev | Volume | 28 |
| Issue | 5 | Pages | 451-62 |
| PubMed ID | 24532689 | Mgi Jnum | J:209141 |
| Mgi Id | MGI:5566550 | Doi | 10.1101/gad.236745.113 |
| Citation | Roset R, et al. (2014) The Rad50 hook domain regulates DNA damage signaling and tumorigenesis. Genes Dev 28(5):451-62 |
| abstractText | 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 Zn(2+)-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 hook-dependent Mre11 complex functions. One of these alleles, Rad50(46), conferred reduced Zn(2+) affinity and dimerization efficiency. Homozygous Rad50(46/46) mutations were lethal in mice. However, in the presence of wild-type Rad50, Rad50(46) 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. |
