BRCA1、BRCA2、RAD51 和其他 DSB 修复因子的表达受 CRL4 调控。
Expression of BRCA1, BRCA2, RAD51, and other DSB repair factors is regulated by CRL4.
机构信息
Laboratory for Cell Biology and Genetics, The Rockefeller University, New York, NY 10065, USA.
Bioinformatics Resource Center, The Rockefeller University, New York, NY 10065, USA.
出版信息
DNA Repair (Amst). 2022 May;113:103320. doi: 10.1016/j.dnarep.2022.103320. Epub 2022 Mar 15.
Double-strand break (DSB) repair relies on DNA damage response (DDR) factors including BRCA1, BRCA2, and RAD51, which promote homology-directed repair (HDR); 53BP1, which affects single-stranded DNA formation; and proteins that mediate end-joining. Here we show that the CRL4/DDB1/WDR70 complex (CRL4) controls the expression of DDR factors. Auxin-mediated degradation of WDR70 led to reduced expression of BRCA1, BRCA2, RAD51, and other HDR factors; 53BP1 and its downstream effectors; and other DDR factors. In contrast, cNHEJ factors were generally unaffected. WDR70 loss abrogated the localization of HDR factors to DSBs and elicited hallmarks of genomic instability, although 53BP1/RIF1 foci still formed. Mutation of the DDB1-binding WD40 motif, disruption of DDB1, or inhibition of cullins phenocopied WDR70 loss, consistent with CRL4, DDB1, and WDR70 functioning as a complex. RNA-sequencing revealed that WDR70 degradation affects the mRNA levels of DDR and many other factors. The data indicate that CRL4 is critical for expression of myriad genes including BRCA1, BRCA2, and RAD51.
双链断裂 (DSB) 修复依赖于 DNA 损伤反应 (DDR) 因子，包括 BRCA1、BRCA2 和 RAD51，它们促进同源定向修复 (HDR)；53BP1 影响单链 DNA 的形成；以及介导末端连接的蛋白质。在这里，我们表明 CRL4/DDB1/WDR70 复合物 (CRL4) 控制 DDR 因子的表达。通过生长素介导的 WDR70 降解导致 BRCA1、BRCA2、RAD51 和其他 HDR 因子的表达减少；53BP1 及其下游效应物；和其他 DDR 因子。相比之下，cNHEJ 因子通常不受影响。WDR70 的缺失消除了 HDR 因子在 DSB 处的定位，并引发了基因组不稳定性的特征，尽管 53BP1/RIF1 焦点仍然形成。DDB1 结合 WD40 基序的突变、DDB1 的破坏或 cullin 的抑制都模拟了 WDR70 的缺失，这与 CRL4、DDB1 和 WDR70 作为一个复合物起作用一致。RNA 测序显示，WDR70 的降解会影响 DDR 和许多其他因子的 mRNA 水平。数据表明，CRL4 对包括 BRCA1、BRCA2 和 RAD51 在内的众多基因的表达至关重要。
Zotero 插件