Tremblay Cédric S, Huang Feng Fei, Lévesque Georges, Carreau Madeleine
Australian Centre for Blood Diseases, Monash University, Melbourne, Australia.
Francis Family Liver Clinic, University Health Network, Toronto, ON, Canada.
BMC Res Notes. 2018 Feb 20;11(1):138. doi: 10.1186/s13104-018-3243-7.
The Hairy Enhancer of Split 1 (HES1) is a transcriptional repressor that regulates cellular proliferation and differentiation during development. We previously found an interaction between HES1 and Fanconi anemia (FA) proteins. FA is a hematological and developmental disorder caused by mutations in more than 20 different genes. Eight FA gene products form a nuclear core complex containing E3 ligase activity required for mono-ubiquitination of FANCD2 and FANCI, both of which are FA proteins. Given that HES1 interacts with members of the FA core complex, the aim of this study was to determine whether HES1 is mono-ubiquitinated via the FA core complex.
We show that HES1 is mono-ubiquitinated on a highly-conserved lysine residue that is located within a FA-like recognition motif. HES1 modification is dependent on a functional FA complex. Absence of HES1 mono-ubiquitination affects transcriptional repression of its own promoter. This study uncovers a novel post-translational modification of HES1 that regulates its transcriptional activity and suggests that ubiquitination of HES1 occurs in a FA core complex-dependent manner.
分裂增强子1（HES1）是一种转录抑制因子，在发育过程中调节细胞增殖和分化。我们之前发现HES1与范可尼贫血（FA）蛋白之间存在相互作用。FA是一种血液学和发育障碍疾病，由20多种不同基因的突变引起。8种FA基因产物形成一个核核心复合物，该复合物含有FANCD2和FANCI单泛素化所需的E3连接酶活性，FANCD2和FANCI均为FA蛋白。鉴于HES1与FA核心复合物成员相互作用，本研究的目的是确定HES1是否通过FA核心复合物发生单泛素化。
我们发现HES1在一个高度保守的赖氨酸残基上发生单泛素化，该残基位于一个类似FA的识别基序内。HES1的修饰依赖于功能性FA复合物。HES1单泛素化的缺失会影响其自身启动子的转录抑制。本研究揭示了一种调节HES1转录活性的新型翻译后修饰，并表明HES1的泛素化以FA核心复合物依赖的方式发生。
