Nucleic Acids Research, Vol 25, Issue 19 3868-3874, Copyright © 1997 by Oxford University Press
S Buchhop, MK Gibson, XW Wang, P Wagner, HW Sturzbecher and CC Harris
p53 is thought to function in the maintenance of genomic stability by
modulating transcription and interacting with cellular proteins to
influence the cell cycle, DNA repair and apoptosis. p53 mutations occur in
>50% of human cancers, and cells which lack wild type p53 accumulate
karyotypic abnormalities such as amplifications, deletions, inversions and
translocations. We propose that p53 hinders these promiscuous
recombinational events by interacting with cellular recombination and
repair machinery. We recently reported that p53 can directly bind in vivo
to human Rad51 (hRad51) protein and in vitro to its bacterial homologue
RecA. We used GST-fusion and his-tagged protein systems to further
investigate the physical interaction between p53 and hRad51, homologue of
the yeast Rad51 protein that is involved in recombination and DNA double
strand repair. The hRad51 binds to wild-type p53 and to a lesser extent,
point mutants 135Y, 249S and 273H. This binding is not mediated by a DNA or
RNA intermediate. Mapping studies using a panel of p53 deletion mutants
indicate that hRad51 could bind to two regions of p53; one between amino
acids 94 and 160 and a second between 264 and 315. Addition of anti-p53
antibody PAb421 (epitope 372-381 amino acids) inhibited the interaction
with hRad51. In contrast, p53 interacts with the region between aa 125 and
220 of hRad51, which is highly conserved among Rad51 related proteins from
bacteria to human. In Escherichia coli ecA protein, this region is required
for homo-oligomerization, suggesting that p53 might disrupt the interaction
between RecA and Rad51 subunits, thus inhibiting biochemical functions of
Rad51 like proteins. These data are consistent with the hypothesis that p53
interaction with hRAD51 may influence DNA recombination and repair and that
additional modifications of p53 by mutation and protein binding may affect
this interaction.
ARTICLES
Interaction of p53 with the human Rad51 protein
Institut fur Humangenetik Universitat zu Lubeck, Ratzeburger Allee 160, D-23538 Lubeck, Germany.
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