Zink Daniele, Mayr Christoph, Janz Christine, Wiesmüller Lisa
Institut für Anthropologie und Humangenetik LMU München, Goethestr. 31,80336 München, Germany.
Oncogene. 2002 Jul 18;21(31):4788-800. doi: 10.1038/sj.onc.1205614.
Our previous recombination and biochemical analyses have led to the hypothesis that the tumor suppressor p53 monitors homologous recombination, a function which was previously attributed to the mismatch repair protein MSH2. Here, we show that a certain fraction of p53 is concentrated within discrete nuclear foci of cells synchronized in G1 phase, a pattern which becomes even more pronounced in S phase, especially after gamma-ray treatment. p53 foci show some colocalization with MSH2 within distinct foci during G1 phase, while dots formed by BRCA1 display an independent localization pattern. In S phase nuclei, p53 foci almost completely colocalize with MSH2 foci and associate with the recombination surveillance factor BRCA1 in irradiated S phase cells. These p53 and MSH2 foci also show significant overlaps with foci of the recombination enzymes Rad50 and Rad51, which for the first time unveiled recombination-related functions of p53 in replicating cells. During S phase, p53 and MSH2 are maximally active in binding to early recombination intermediates, and coexist within the same nuclear DNA-protein complexes. Our data suggest that p53 is linked similarly to homologous recombination as MSH2 and provide further evidence for the new concept of a dual role of p53 in the regulation of growth and repair.
我们之前的重组和生化分析得出了一个假说，即肿瘤抑制因子p53监测同源重组，而这一功能此前被认为是错配修复蛋白MSH2的作用。在此，我们发现，在G1期同步化的细胞中，一定比例的p53集中在离散的核灶内，这种模式在S期变得更加明显，尤其是在γ射线处理后。在G1期，p53灶与MSH2在不同的灶内有部分共定位，而由BRCA1形成的点显示出独立的定位模式。在S期细胞核中，p53灶几乎完全与MSH2灶共定位，并在受辐射的S期细胞中与重组监测因子BRCA1相关联。这些p53和MSH2灶也与重组酶Rad50和Rad51的灶有显著重叠，这首次揭示了p53在复制细胞中的重组相关功能。在S期，p53和MSH2在与早期重组中间体结合方面活性最高，并共存于同一核DNA-蛋白质复合物中。我们的数据表明，p53与同源重组的关联方式与MSH2类似，并为p53在生长和修复调节中的双重作用这一新概念提供了进一步的证据。
