Sy Shirley M-H, Huen Michael S Y, Zhu Yongyou, Chen Junjie
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
J Biol Chem. 2009 Jul 3;284(27):18302-10. doi: 10.1074/jbc.M109.016717. Epub 2009 May 7.
Maintenance of genomic stability ensures faithful transmission of genetic information and helps suppress neoplastic transformation and tumorigenesis. Although recent progress has advanced our understanding of DNA damage checkpoint regulations, little is known as to how DNA repair, especially the RAD51-dependent homologous recombination repair pathway, is executed in vivo. Here, we reveal novel properties of the BRCA2-associated protein PALB2 in the assembly of the recombinational DNA repair machinery at DNA damage sites. Although the chromatin association of PALB2 is a prerequisite for subsequent BRCA2 and RAD51 loading, the focal accumulation of the PALB2 x BRCA2 x RAD51 complex at DSBs occurs independently of known DNA damage checkpoint and repair proteins. We provide evidence to support that PALB2 exists as homo-oligomers and that PALB2 oligomerization is essential for its focal accumulation at DNA breaks in vivo. We propose that both PALB2 chromatin association and its oligomerization serve to secure the BRCA2 x RAD51 repair machinery at the sites of DNA damage. These attributes of PALB2 are likely instrumental for proficient homologous recombination DNA repair in the cell.
基因组稳定性的维持确保了遗传信息的忠实传递，并有助于抑制肿瘤转化和肿瘤发生。尽管最近的进展增进了我们对DNA损伤检查点调控的理解，但对于DNA修复，尤其是RAD51依赖的同源重组修复途径在体内是如何执行的，我们却知之甚少。在此，我们揭示了BRCA2相关蛋白PALB2在DNA损伤位点的重组DNA修复机制组装中的新特性。虽然PALB2与染色质的结合是随后BRCA2和RAD51加载的先决条件，但PALB2 x BRCA2 x RAD51复合物在双链断裂（DSBs）处的焦点聚集独立于已知的DNA损伤检查点和修复蛋白而发生。我们提供证据支持PALB2以同源寡聚体形式存在，并且PALB2寡聚化对于其在体内DNA断裂处的焦点聚集至关重要。我们提出，PALB2与染色质的结合及其寡聚化都有助于在DNA损伤位点确保BRCA2 x RAD51修复机制的存在。PALB2的这些特性可能对细胞中高效的同源重组DNA修复起重要作用。
