Kantake Noriko, Sugiyama Tomohiko, Kolodner Richard D, Kowalczykowski Stephen C
Sections of Microbiology and of Molecular and Cellular Biology, Center for Genetics and Development, University of California, Davis, California 95616, USA.
J Biol Chem. 2003 Jun 27;278(26):23410-7. doi: 10.1074/jbc.M302995200. Epub 2003 Apr 14.
Replication protein-A (RPA) is involved in many processes of DNA metabolism, including DNA replication, repair, and recombination. Cells carrying a mutation in the largest subunit of RPA (rfa1-t11: K45E) have defects in meiotic recombination, mating-type switching, and survival after DNA damage caused by UV and methyl methanesulfonate, as well as increased genome instability; however, this mutant has no significant defect in DNA replication. We purified the RPA heterotrimer containing the rfa1-t11 substitution (RPA(rfa1-t11)). This mutant RPA binds single-stranded DNA (ssDNA) with the same site size, and the RPA(rfa1-t11).ssDNA complex shows a similar sensitivity to disruption by salt as the wild-type RPA.ssDNA complex. RPA(rfa1-t11) stimulates DNA strand exchange, provided that the Rad51 protein.ssDNA nucleoprotein complex is assembled prior to introduction of the mutant RPA. However, RPA(rfa1-t11) is displaced from ssDNA by Rad51 protein more slowly than wild-type RPA and, as a consequence, Rad51 protein-mediated DNA strand exchange is inhibited when the ssDNA is in a complex with RPA(rfa1-t11). Rad52 protein can stimulate displacement of RPA(rfa1-t11) from ssDNA by Rad51 protein, but the rate of displacement remains slow compared with wild-type RPA. These in vitro results suggest that, in vivo, RPA is bound to ssDNA prior to Rad51 protein and that RPA displacement by Rad51 protein is a critical step in homologous recombination, which is impaired in the rfa1-t11 mutation.
复制蛋白A(RPA)参与DNA代谢的许多过程,包括DNA复制、修复和重组。携带RPA最大亚基突变(rfa1 - t11:K45E)的细胞在减数分裂重组、交配型转换以及紫外线和甲磺酸甲酯引起的DNA损伤后的存活方面存在缺陷,并且基因组不稳定性增加;然而,该突变体在DNA复制方面没有明显缺陷。我们纯化了含有rfa1 - t11替代的RPA异源三聚体(RPA(rfa1 - t11))。这种突变型RPA以相同的位点大小结合单链DNA(ssDNA),并且RPA(rfa1 - t11).ssDNA复合物对盐破坏的敏感性与野生型RPA.ssDNA复合物相似。只要在引入突变型RPA之前组装了Rad51蛋白.ssDNA核蛋白复合物,RPA(rfa1 - t11)就会刺激DNA链交换。然而,RPA(rfa1 - t11)从ssDNA被Rad51蛋白取代的速度比野生型RPA慢,因此,当ssDNA与RPA(rfa1 - t11)形成复合物时,Rad51蛋白介导的DNA链交换受到抑制。Rad52蛋白可以刺激Rad51蛋白将RPA(rfa1 - t11)从ssDNA上取代,但与野生型RPA相比,取代速度仍然较慢。这些体外结果表明,在体内,RPA在Rad51蛋白之前与ssDNA结合,并且Rad51蛋白取代RPA是同源重组中的关键步骤,而rfa1 - t11突变会损害这一步骤。