1: Carcinogenesis. 2004 Aug;25(8):1305-13. Epub 2004 Jan 23. 

Recombination at chromosomal sequences involved in leukaemogenic rearrangements
is differentially regulated by p53.

Boehden GS, Restle A, Marschalek R, Stocking C, Wiesmuller L.

Universitatsfrauenklinik, Prittwitzstrasse 43, D-89075 Ulm, Johann Wolfgang
Goethe Universitat, Biozentrum, N230, R303, Marie-Curie-Strasse 9, D-60439
Frankfurt/Main, Germany.

Chromosomal translocations and retroviral integration events at breakpoint
cluster regions (bcrs) have been associated with leukaemias. To directly compare
the effect of different cis-regulatory sequences on recombination, we adapted
our SV40 based model system to the analysis of correspondingly selected bcrs
from the TAL1, LMO2, retinoic acid receptor alpha (RARalpha) and MLL genes. We
show that a 399 bp fragment from the MLL bcr is sufficient to cause a 3-4-fold
stimulation of spontaneously occurring DNA exchange and to respond to etoposide
by up to 10-fold further elevated frequencies, i.e. to mimic the fragility of
the 8.3 kb bcr during chemotherapy. To analyse the regulatory role of p53 in
recombination involving leukaemia-related sequences, we stably expressed wtp53
and a transactivation negative mutant. Consistent with the proposed role of p53
as a suppressor of error-prone recombination, both p53 proteins down-regulated
recombination with most of the sequences tested, even with the MLL bcr after
etoposide treatment. Surprisingly, however, p53 stimulated recombination, in
constructs carrying the RARalpha bcr fragment. This is the first study, which
provides evidence for a stimulatory role of p53 in homologous recombination. Our
data further indicate that inhibition of topoisomerase I can mimic the effects
of p53 on stimulating recombination on the RARalpha bcr. Thus, these data also
firstly describe a biological role of the biochemical interactions between p53
and topoisomerase I that may have implications for a gain-of-function phenotype
of certain p53 mutants in genetic destabilization.

PMID: 14742315 [PubMed - indexed for MEDLINE]


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