Human and mouse homologs of Schizosaccharomyces pombe rad1(+) and Saccharomyces cerevisiae RAD17: linkage to checkpoint control and mammalian meiosis.
Preventing or delaying progress through the cell cycle in response to DNA damage is crucial for eukaryotic cells to allow the damage to be repaired and not incorporated irrevocably into daughter cells. Several genes involved in this process have been discovered in fission and budding yeast. Here, we report the identification of human and mouse homologs of the Schizosaccharomyces pombe DNA damage checkpoint control gene rad1(+) and its Saccharomyces cerevisiae homolog RAD17. The human gene HRAD1 is located on chromosome 5p13 and is most homologous to S. pombe rad1(+). This gene encodes a 382-amino-acid residue protein that is localized mainly in the nucleus and is expressed at high levels in proliferative tissues. This human gene significantly complements the sensitivity to UV light of a S. pombe strain mutated in rad1(+). Moreover, HRAD1 complements the checkpoint control defect of this strain after UV exposure. In addition to functioning in DNA repair checkpoints, S. cerevisiae RAD17 plays a role during meiosis to prevent progress through prophase I when recombination is interrupted. Consistent with a similar role in mammals, Rad1 protein is abundant in testis, and is associated with both synapsed and unsynapsed chromosomes during meiotic prophase I of spermatogenesis, with a staining pattern distinct from that of the recombination proteins Rad51 and Dmc1. Together, these data imply an important role for hRad1 both in the mitotic DNA damage checkpoint and in meiotic checkpoint mechanisms, and suggest that these events are highly conserved from yeast to humans.
Wellcome Trust/Cancer Research Campaign Institute of Cancer and Developmental Biology, and Department of Zoology, Cambridge University, Cambridge CB2 1QR, UK.
R
R
Freire
J R
JR
Murguía
M
M
Tarsounas
N F
NF
Lowndes
P B
PB
Moens
S P
SP
Jackson
D000595:Amino Acid Sequence; D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins / Q000737:chemistry; D002467:Cell Nucleus / Q000378:metabolism; D002874:Chromosome Mapping; D004249:DNA Damage; D004260:DNA Repair; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins; D004720:Endonucleases / Q000737:chemistry; D005092:Exonucleases / Q000502:physiology*; D005656:Fungal Proteins / Q000737:chemistry; D015870:Gene Expression; D005816:Genetic Complementation Test; D006367:HeLa Cells; D006801:Humans; D008297:Male; D008540:Meiosis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins; D011418:Prophase; D051381:Rats; D012441:Saccharomyces cerevisiae / Q000737:chemistry / Q000166:cytology / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins; D012568:Schizosaccharomyces / Q000737:chemistry / Q000235:genetics; D029702:Schizosaccharomyces pombe Proteins; D017386:Sequence Homology, Amino Acid; D013091:Spermatogenesis / Q000235:genetics / Q000502:physiology; D013737:Testis / Q000166:cytology / Q000502:physiology; D015854:Up-Regulation
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; D009687:Nuclear Proteins; C501395:RAD17 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D029702:Schizosaccharomyces pombe Proteins; D004720:Endonucleases; D005092:Exonucleases; C069266:RAD1 protein, S cerevisiae; C499354:rad1 protein, S pombe; C113574:Rad1 protein, human; D045643:DNA Repair Enzymes