Frag1, a homolog of alternative replication factor C subunits, links replication stress surveillance with apoptosis.
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.
Ishii
Hideshi
H
Center for Molecular Medicine, Jichi Medical School, Tochigi 329-0498, Japan.
Inageta
Taeko
T
Mimori
Koshi
K
Saito
Toshiyuki
T
Sasaki
Hiroki
H
Isobe
Masaharu
M
Mori
Masaki
M
Croce
Carlo M
CM
Huebner
Kay
K
Ozawa
Keiya
K
Furukawa
Yusuke
Y
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D064007:Ataxia Telangiectasia Mutated Proteins; D001483:Base Sequence; D015152:Blotting, Northern; D001973:Bromodeoxyuridine; D018797:Cell Cycle Proteins / Q000378:metabolism; D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics*; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D042822:Genomic Instability / Q000235:genetics*; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010957:Plasmids / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D016196:S Phase / Q000502:physiology; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000235:genetics*; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; C494827:Bax protein, mouse; D018797:Cell Cycle Proteins; D002843:Chromatin; C503454:FRAG1 protein, mouse; D009687:Nuclear Proteins; C484441:PGAP2 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D051028:bcl-2-Associated X Protein; C069930:rad9 protein; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D001973:Bromodeoxyuridine