Institute of Genetics and Cancer

The importance of enzymatic activity does not always ‘RING’ true

Scientists from the MRC Human Genetics Unit have proved new things about Protein RING1B: October 2015

When a protein is shown to have the ability to catalyse a chemical reaction – i.e. to act as an enzyme, the assumption is often made that this is what its biological function is. Scientists from the MRC Human Genetics Unit have shown that this assumption can be wrong. They have shown that RING1B, a protein required for embryonic development in mammals, is able to fulfil many of its biological functions even in the absence of its ability to act as an enzyme.

Gastrulation is a very early phase of embryo development during which the three principle tissue types of the adult are generated. Central to this process is a family of gene repressors, collectively known as polycomb proteins. Deficiency of RING1B, a core component of this regulatory system, prevents mouse embryos from completing gastrulation. At the molecular level, RING1B remodels chromatin, both via direct chemical modification and by mechanical compaction. However, until now, which of these functions is essential for early embryonic development was unknown.

To address this question, Illingworth and colleagues engineered mouse embryonic stem cells to expresses a stable, but catalytically inactivate, form of RING1B. Cells carrying this mutation had near normal gene expression, despite lacking the ability to chemically modify chromatin. Mouse embryos derived from these RING1B mutant cells were able to complete gastrulation and to continue apparently quite normal development until much later in embryogenesis. These findings suggest that the catalytic activity of RING1B is largely dispensable for early mammalian development.  

Our findings highlight the importance of dissecting out enzymatic versus structural roles when trying to understand the function of essential proteins

Doctor Robert IllingworthMRC Human Genetics Unit, IGMM 

The study is published in the journal Genes and Development and was funded by the Medical Research Council. 

The E3 ubiquitin ligase activity of RING1B is not essential for early mouse development. 

Illingworth RSMoffat M, Mann AR, Read D, Hunter CJ, Pradeepa MM, Adams IR, Bickmore WA. Genes Dev. 2015 Sep 15;29(18):1897-902. doi: 10.1101/gad.268151.115.