Advanced Centre for Treatment, Research and Education in Cancer, Kharghar, Navi Mumbai, Maharashtra, India.
PLoS One. 2013 Sep 9;8(9):e72707. doi: 10.1371/journal.pone.0072707. eCollection 2013.
Receptor Associated Protein 80 (RAP80) is a member of RAP80-BRCA1-CCDC98 complex family and helps in its recruitment to the DNA damage site for effective homologous recombination repair. It encompasses two tandem UIMs (UIM1 and UIM2) motif at its N-terminus, which interact with K-63 linked polyubiquitin chain(s) on H2AX and thereby assemble the RAP80-BRCA1 complex at the damage site. Nevertheless, how RAP80 helps in the structural integrity of BRCA1 complex is still elusive. Considering the role of RAP80 in the recruitment of BRCA1 complex at the DNA damage site, we attempted to explore the molecular mechanism associated with RAP80 and mutation that causes chromosomal aberrations due to its loss of function. There is a significant loss in structural characteristics of RAP80 ΔE81, which impairs its binding affinity with the polyubiquitin chain. This leads to the defective recruitment of RAP80 and BRCA1 complex at the DNA damage site. The results presented here are very useful in understanding the cause of various repair defects (chromosomal aberration) that arise due to this mutation. Comparative study of wild type and ΔE81 could be helpful in designing the small molecules that can potentially compensate the deleterious effect(s) of ΔE81 and hence useful for therapeutic application.
受体相关蛋白 80（RAP80）是 RAP80-BRCA1-CCDC98 复合物家族的成员，有助于其募集到 DNA 损伤部位，进行有效的同源重组修复。它在 N 端包含两个串联的 UIM（UIM1 和 UIM2）基序，与 H2AX 上的 K-63 连接多泛素链相互作用，从而在损伤部位组装 RAP80-BRCA1 复合物。然而，RAP80 如何帮助 BRCA1 复合物保持结构完整性仍不清楚。考虑到 RAP80 在 DNA 损伤部位募集 BRCA1 复合物中的作用，我们试图探索与 RAP80 相关的分子机制及其突变，因为其功能丧失会导致染色体异常。RAP80 ΔE81 的结构特征显著丧失，这会损害其与多泛素链的结合亲和力。这导致 RAP80 和 BRCA1 复合物在 DNA 损伤部位的募集缺陷。这里呈现的结果对于理解由于这种突变导致的各种修复缺陷（染色体异常）的原因非常有用。野生型和 ΔE81 的比较研究可能有助于设计潜在的小分子，以补偿 ΔE81 的有害影响，因此对治疗应用有用。
