p53 Activity Results in DNA Replication Fork Processivity.
p53 induces cell death upon DNA damage, but this may not confer all of its tumor suppressor activity. We report that p53 activation enhances the processivity of DNA replication, as monitored by multi-label fiber assays, whereas removal of p53 reduces fork progression. This is observed in tumor-derived U2OS cells but also in murine embryonic fibroblasts with heterozygous or homozygous p53 deletion and in freshly isolated thymocytes from mice with differential p53 status. Mdm2, a p53-inducible gene product, similarly supports DNA replication even in p53-deficient cells, suggesting that sustained Mdm2-expression is at least one of the mechanisms allowing p53 to prevent replicative stress. Thus, p53 helps to protect the genome during S phase, by preventing the occurrence of stalled or collapsed replication forks. These results expand p53's tumor-suppressive functions, adding to the ex-post model (elimination of damaged cells) an ex-ante activity; i.e., the prevention of DNA damage during replication.
Institute of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center Göttingen, 37077 Göttingen, Germany.
Ina
I
Klusmann
Institute of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center Göttingen, 37077 Göttingen, Germany.
Sabrina
S
Rodewald
Institute of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center Göttingen, 37077 Göttingen, Germany.
Leonie
L
Müller
Institute of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center Göttingen, 37077 Göttingen, Germany.
Mascha
M
Friedrich
Institute of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center Göttingen, 37077 Göttingen, Germany.
Magdalena
M
Wienken
Institute of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center Göttingen, 37077 Göttingen, Germany.
Yizhu
Y
Li
Institute of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center Göttingen, 37077 Göttingen, Germany.
Ramona
R
Schulz-Heddergott
Institute of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center Göttingen, 37077 Göttingen, Germany. Electronic address: mdobbel@uni-goettingen.de.
Matthias
M
Dobbelstein
D000818:Animals; D004261:DNA Replication / Q000235:genetics; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D016399:Lymphoma, T-Cell / Q000473:pathology; D051379:Mice; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D016196:S Phase / Q000235:genetics; D060168:Thymocytes / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000378:metabolism*
D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2