Mammalian Rad9 plays a role in telomere stability, S- and G2-phase-specific cell survival, and homologous recombinational repair.
The protein products of several rad checkpoint genes of Schizosaccharomyces pombe (rad1+, rad3+, rad9+, rad17+, rad26+, and hus1+) play crucial roles in sensing changes in DNA structure, and several function in the maintenance of telomeres. When the mammalian homologue of S. pombe Rad9 was inactivated, increases in chromosome end-to-end associations and frequency of telomere loss were observed. This telomere instability correlated with enhanced S- and G2-phase-specific cell killing, delayed kinetics of gamma-H2AX focus appearance and disappearance, and reduced chromosomal repair after ionizing radiation (IR) exposure, suggesting that Rad9 plays a role in cell cycle phase-specific DNA damage repair. Furthermore, mammalian Rad9 interacted with Rad51, and inactivation of mammalian Rad9 also resulted in decreased homologous recombinational (HR) repair, which occurs predominantly in the S and G2 phases of the cell cycle. Together, these findings provide evidence of roles for mammalian Rad9 in telomere stability and HR repair as a mechanism for promoting cell survival after IR exposure.
Department of Radiation Oncology, Washington University School of Medicine, 4511 Forest Park Ave., St. Louis, MO 63108, USA. pandita@wustl.edu
Raj K
RK
Pandita
Girdhar G
GG
Sharma
Andrei
A
Laszlo
Kevin M
KM
Hopkins
Scott
S
Davey
Mikhail
M
Chakhparonian
Arun
A
Gupta
Raymund J
RJ
Wellinger
Junran
J
Zhang
Simon N
SN
Powell
Joseph L
JL
Roti Roti
Howard B
HB
Lieberman
Tej K
TK
Pandita
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle / Q000235:genetics* / Q000528:radiation effects; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000235:genetics; D064447:Checkpoint Kinase 2; D002869:Chromosome Aberrations; D004247:DNA / Q000235:genetics / Q000378:metabolism / Q000528:radiation effects; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism; D016195:G2 Phase / Q000235:genetics / Q000528:radiation effects; D006657:Histones / Q000235:genetics / Q000378:metabolism / Q000528:radiation effects; D006801:Humans; D008322:Mammals; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011839:Radiation, Ionizing; D011995:Recombination, Genetic; D016196:S Phase / Q000235:genetics / Q000528:radiation effects; D029702:Schizosaccharomyces pombe Proteins; D035182:TATA Box Binding Protein-Like Proteins / Q000378:metabolism; D016615:Telomere / Q000235:genetics* / Q000528:radiation effects; D035341:Telomeric Repeat Binding Protein 2; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D006657:Histones; D009687:Nuclear Proteins; D029702:Schizosaccharomyces pombe Proteins; D035182:TATA Box Binding Protein-Like Proteins; C504753:TERF2 protein, human; D035341:Telomeric Repeat Binding Protein 2; D025521:Tumor Suppressor Proteins; C069930:rad9 protein; D004247:DNA; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C578634:CHEK2 protein, human; C578636:Cds1 protein, S pombe; D017346:Protein Serine-Threonine Kinases