Mammalian Rif1 contributes to replication stress survival and homology-directed repair.
Rif1, originally recognized for its role at telomeres in budding yeast, has been implicated in a wide variety of cellular processes in mammals, including pluripotency of stem cells, response to double-strand breaks, and breast cancer development. As the molecular function of Rif1 is not known, we examined the consequences of Rif1 deficiency in mouse cells. Rif1 deficiency leads to failure in embryonic development, and conditional deletion of Rif1 from mouse embryo fibroblasts affects S-phase progression, rendering cells hypersensitive to replication poisons. Rif1 deficiency does not alter the activation of the DNA replication checkpoint but rather affects the execution of repair. RNA interference to human Rif1 decreases the efficiency of homology-directed repair (HDR), and Rif1 deficiency results in aberrant aggregates of the HDR factor Rad51. Consistent with a role in S-phase progression, Rif1 accumulates at stalled replication forks, preferentially around pericentromeric heterochromatin. Collectively, these findings reveal a function for Rif1 in the repair of stalled forks by facilitating HDR.
Buonomo
Sara B C
SB
Laboratory of Cell Biology and Genetics, The Rockefeller University, New York, NY 10065, USA. sara.buonomo@embl.it
Wu
Yipin
Y
Ferguson
David
D
de Lange
Titia
T
D000818:Animals; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication; D047108:Embryonic Development / Q000235:genetics; D006570:Heterochromatin; D006801:Humans; D051379:Mice; D034622:RNA Interference; D051135:Rad51 Recombinase / Q000378:metabolism; D016196:S Phase / Q000235:genetics; D034501:Telomere-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D006570:Heterochromatin; C492748:Rif1 protein, mouse; D034501:Telomere-Binding Proteins; D051135:Rad51 Recombinase