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Published online
doi:10.1083/jcb.200902039
The Journal of Cell Biology, Vol. 187, No. 3, 385-398
The Rockefeller University Press, 0021-9525 $30.00
© Buonomo et al.
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Article

Mammalian Rif1 contributes to replication stress survival and homology-directed repair



Sara B.C. Buonomo1, Yipin Wu2, David Ferguson2, and Titia de Lange1

1 Laboratory of Cell Biology and Genetics, The Rockefeller University, New York, NY 10065
2 Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109

Correspondence to Sara B.C. Buonomo: sara.buonomo{at}embl.it

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.

Abbreviations used in this paper: ATM, ataxia telangiectasia mutated; ATR, ataxia telangiectasia and Rad3 related; DSB, double-strand break; ES, embryonic stem; HDR, homology-directed repair; HU, hydroxyurea; IF, immunofluorescence; IR, ionizing radiation; LTGC, long tract gene conversion; MEF, mouse embryonic fibroblast; MMC, mitomycin C; mTOR, mammalian target of rapamycin; NeoR, Neomycin resistance; shRNA, short hairpin RNA; SKY, spectral karyotyping analysis; ssDNA, single-stranded DNA; SV40LT, SV40 large T antigen.

© 2009 Buonomo et al.
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