Frag1, a homolog of alternative replication factor C subunits, links replication stress surveillance with apoptosis

Hideshi Ishii, Taeko Inageta, Koshi Mimori, Toshiyuki Saito, Hiroki Sasaki, Masaharu Isobe, Masaki Mori, Carlo M. Croce, Kay Huebner, Keiya Ozawa, Yusuke Furukawa

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Abstract

We report the identification and characterization of a potent regulator of genomic integrity, mouse and human FRAG1 gene, a conserved homolog of replication factor C large subunit that is homologous to the alternative replication factor C subunits Elg1, Ctf18/Chl12, and Rad24 of budding yeast. FRAG1 was identified in a search for key caretaker genes involved in the regulation of genomic stability under conditions of replicative stress. In response to stress, Atr participates in the down-regulation of FRAG1 expression, leading to the induction of apoptosis through the release of Rad9 from damaged chromatin during the S phase of the cell cycle, allowing Rad9-Bcl2 association and induction of proapoptotic Bax protein. We propose that the Fragt signal pathway, by linking replication stress surveillance with apoptosis induction, plays a central role in determining whether DNA damage is compatible with cell survival or whether it requires cell elimination by apoptosis.

Original languageEnglish
Pages (from-to)9655-9660
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number27
DOIs
Publication statusPublished - Jul 5 2005

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