Open AccessFrag1, a homolog of alternative replication factor C subunits, links replication stress surveillance with apoptosis
Author(s) -
Hideshi Ishii,
Taeko Inageta,
Koshi Mimori,
Toshiyuki Saito,
Hiroki Sasaki,
Masaharu Isobe,
Masaki Mori,
Carlo M. Croce,
Kay Huebner,
Keiya Ozawa,
Yusuke Furukawa
Publication year - 2005
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0504222102
Subject(s) - biology , replication factor c , microbiology and biotechnology , origin recognition complex , dna replication factor cdt1 , dna replication , cell cycle , control of chromosome duplication , eukaryotic dna replication , genetics , dna damage , protein subunit , cell cycle checkpoint , regulator , gene , dna
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 Frag1 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.