p53 mutated in the transactivation domain retains regulatory functions in homology-directed double-strand break repair
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p53 mutated in the transactivation domain retains regulatory functions in homology-directed double-strand break repair. / Boehden, Gisa S; Akyüz, Nuray; Roemer, Klaus; Wiesmüller, Lisa.
In: ONCOGENE, Vol. 22, No. 26, 26.06.2003, p. 4111-7.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - p53 mutated in the transactivation domain retains regulatory functions in homology-directed double-strand break repair
AU - Boehden, Gisa S
AU - Akyüz, Nuray
AU - Roemer, Klaus
AU - Wiesmüller, Lisa
PY - 2003/6/26
Y1 - 2003/6/26
N2 - The tumor suppressor p53 transcriptionally transactivates cellular target genes that are implicated in growth control, apoptosis, and DNA repair. However, several studies involving p53 core domain mutants suggested that regulatory functions in recombinative repair do not require transcriptional transactivation and are separable from growth-regulation and apoptosis. Leu22 and Trp23 within the transactivation domain of human p53 play a critical role in binding basal components of the transcription machinery and, therefore, in the transactivation activity of p53. To further delineate whether p53 target genes are involved in recombination regulation, we ectopically expressed p53(22Q,23S) in p53-negative cell lines, which carry reporter systems for different homology-directed double-strand break (DSB) repair events. Like wild-type p53, p53(22Q,23S) efficiently downregulated homologous recombination on two chromosomally integrated substrates without affecting exchange on a substrate for the compound pathway of gene conversion and nonhomologous end joining. Only upon lowering the p53 protein to DNA substrate ratio by several orders of magnitude, we noticed a weak defect of a p53 transactivation domain mutant in DSB repair assays. In conclusion, molecular interactions of p53 within the N-terminal domain are not required to restrain DNA recombination, but might contribute to this genome stabilizing function.
AB - The tumor suppressor p53 transcriptionally transactivates cellular target genes that are implicated in growth control, apoptosis, and DNA repair. However, several studies involving p53 core domain mutants suggested that regulatory functions in recombinative repair do not require transcriptional transactivation and are separable from growth-regulation and apoptosis. Leu22 and Trp23 within the transactivation domain of human p53 play a critical role in binding basal components of the transcription machinery and, therefore, in the transactivation activity of p53. To further delineate whether p53 target genes are involved in recombination regulation, we ectopically expressed p53(22Q,23S) in p53-negative cell lines, which carry reporter systems for different homology-directed double-strand break (DSB) repair events. Like wild-type p53, p53(22Q,23S) efficiently downregulated homologous recombination on two chromosomally integrated substrates without affecting exchange on a substrate for the compound pathway of gene conversion and nonhomologous end joining. Only upon lowering the p53 protein to DNA substrate ratio by several orders of magnitude, we noticed a weak defect of a p53 transactivation domain mutant in DSB repair assays. In conclusion, molecular interactions of p53 within the N-terminal domain are not required to restrain DNA recombination, but might contribute to this genome stabilizing function.
KW - Apoptosis
KW - DNA Damage
KW - DNA Repair
KW - Down-Regulation
KW - Genes, p53
KW - Green Fluorescent Proteins
KW - Humans
KW - K562 Cells
KW - Leucine
KW - Luminescent Proteins
KW - Models, Biological
KW - Mutation
KW - Protein Structure, Tertiary
KW - Recombination, Genetic
KW - Transcriptional Activation
KW - Tryptophan
U2 - 10.1038/sj.onc.1206632
DO - 10.1038/sj.onc.1206632
M3 - SCORING: Journal article
C2 - 12821945
VL - 22
SP - 4111
EP - 4117
JO - ONCOGENE
JF - ONCOGENE
SN - 0950-9232
IS - 26
ER -