Paul Atanu, Wang Bin
Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Genes and Development Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Genes and Development Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
Mol Cell. 2017 May 18;66(4):458-472.e5. doi: 10.1016/j.molcel.2017.04.013.
Ubiquitin modification of proteins plays pivotal roles in the cellular response to DNA damage. Given the complexity of ubiquitin conjugation due to the formation of poly-conjugates of different linkages, functional roles of linkage-specific ubiquitin modification at DNA damage sites are largely unclear. We identify that Lys11-linkage ubiquitin modification occurs at DNA damage sites in an ATM-dependent manner, and ubiquitin-modifying enzymes, including Ube2S E2-conjugating enzyme and RNF8 E3 ligase, are responsible for the assembly of Lys11-linkage conjugates on damaged chromatin, including histone H2A/H2AX. We show that RNF8- and Ube2S-dependent Lys11-linkage ubiquitin conjugation plays an important role in regulating DNA damage-induced transcriptional silencing, distinct from the role of Lys63-linkage ubiquitin in the recruitment of DNA damage repair proteins 53BP1 and BRCA1. Thus, our study highlights the importance of linkage-specific ubiquitination at DNA damage sites, and it reveals that Lys11-linkage ubiquitin modification plays a crucial role in the DNA damage response.
蛋白质的泛素修饰在细胞对DNA损伤的反应中起着关键作用。由于不同连接方式的多聚泛素缀合物的形成，泛素缀合过程较为复杂，因此DNA损伤位点处连接特异性泛素修饰的功能作用在很大程度上尚不清楚。我们发现，K11连接的泛素修饰以依赖ATM的方式发生在DNA损伤位点，并且包括Ube2S E2缀合酶和RNF8 E3连接酶在内的泛素修饰酶负责在受损染色质（包括组蛋白H2A/H2AX）上组装K11连接的缀合物。我们表明，RNF8和Ube2S依赖的K11连接的泛素缀合在调节DNA损伤诱导的转录沉默中起重要作用，这与K63连接的泛素在募集DNA损伤修复蛋白53BP1和BRCA1中的作用不同。因此，我们的研究突出了DNA损伤位点处连接特异性泛素化的重要性，并揭示了K11连接的泛素修饰在DNA损伤反应中起关键作用。
