Abstract
BLM, WRN, and p53 are involved in the homologous DNA recombination pathway. The DNA structure-specific helicases, BLM and WRN, unwind Holliday junctions (HJ), an activity that could suppress inappropriate homologous recombination during DNA replication. Here, we show that purified, recombinant p53 binds to BLM and WRN helicases and attenuates their ability to unwind synthetic HJ in vitro. The p53 248W mutant reduces abilities of both to bind HJ and inhibit helicase activities, whereas the p53 273H mutant loses these abilities. Moreover, full-length p53 and a C-terminal polypeptide (residues 373-383) inhibit the BLM and WRN helicase activities, but phosphorylation at Ser(376) or Ser(378) completely abolishes this inhibition. Following blockage of DNA replication, Ser(15) phospho-p53, BLM, and RAD51 colocalize in nuclear foci at sites likely to contain DNA replication intermediates in cells. Our results are consistent with a novel mechanism for p53-mediated regulation of DNA recombinational repair that involves p53 post-translational modifications and functional protein-protein interactions with BLM and WRN DNA helicases.
Highlights
BLM, WRN, and p53 are involved in the homologous DNA recombination pathway
Holliday junctions (HJ) arise as intermediates during Homologous recombination (HR) and can occur spontaneously, or during DNA replication and the repair of DNA damage [12]
Evidence of p53 modulation of HR includes the following: (a) overexpression of wild-type p53 (WT p53) can down-regulate the rate of HR between SV40 molecules [15]; (b) the rate of HR is increased in p53 mutant cell lines (16 –18); (c) p53 has 3Ј to 5Ј exonuclease and DNA strand transfer activities [19]; and (d) p53 can bind and inhibit human RAD51 and bacterial RecA, central components of the HR pathway [20, 21]
Summary
Vol 277, No 35, Issue of August 30, pp. 31980 –31987, 2002 Printed in U.S.A. The Processing of Holliday Junctions by BLM and WRN Helicases Is Regulated by p53*□S. The DNA structure-specific helicases, BLM and WRN, unwind Holliday junctions (HJ), an activity that could suppress inappropriate homologous recombination during DNA replication. Evidence of p53 modulation of HR includes the following: (a) overexpression of wild-type p53 (WT p53) can down-regulate the rate of HR between SV40 molecules [15]; (b) the rate of HR is increased in p53 mutant cell lines (16 –18); (c) p53 has 3Ј to 5Ј exonuclease and DNA strand transfer activities [19]; and (d) p53 can bind and inhibit human RAD51 and bacterial RecA, central components of the HR pathway [20, 21]. This paper is available on line at http://www.jbc.org p53 Modulates BLM and WRN Helicase Activities.
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