Study reveals central role played by DBIRD protein complex in gene transcription

In a study published this week in the journal Nature, researchers at the University of Liège's GIGA Unit (www.giga.ulg.ac.be), together with English and German teams, reveal the central role played by a protein complex, unknown up to now, in gene transcription. This research work brings to light a new mechanism for protein diversity whose deregulation could contribute to tumour development.

A cascade of multiple and diverse molecular reactions take place between the gene and the synthesis of a protein. This transcriptional machinery is complex and precisely regulated. DNA is transcribed into a messenger RNA through the action of RNA polymerase II and a series of other regulating proteins. Once synthesised, this messenger RNA will be subjected to other modifications, including splicing, a new molecular stage, which will only retain certain fragments of messenger RNA, the exons. The messenger RNA, once 'mature', becomes the genuine support for coding information underlying the synthesis of proteins.

Splicing can enable the generation of different populations of messenger RNAs from the same gene. This alternative splicing thus constitutes a means of increasing protein variability, allowing human beings to adapt to their environment. This regulation stage is today considered as vital by researchers because it appears that its deregulation can be directly responsible for certain human diseases, such as cancers and neuro-degenerative diseases.

Investigating in particular the mechanisms which regulate alternative splicing, the researchers at the University of Liège's GIGA research unit have brought to light a new protein complex, unknown up to now, and which they have named DBIRD. This complex is situated at the interface between still immature messenger RNA and RNA polymerase II. It is composed of two proteins, Deleted in Breast Cancer protein 1 (DBC1) and ZIRD (ZNF-protein Interacting with nuclear RNPs and DBC1).

Pierre Close, a FNRS Postdoctoral Researcher at the GIGA-ULg and the first author of this study, explains: 'Our analyses have highlighted that, if the DBIRD complex is not directly necessary for the expression of the majority of genes, its absence on the other hand destabilises the splicing reaction of a large number of genes. We demonstrate that the presence of DBIRD is required for RNA polymerase II to play its role adequately, in particular in excluding exons which are rich in A/T nucleotides (adenine and thymine).'

Generally speaking, this study brings to light a new mechanism for controlling the splicing reaction through the regulation of RNA polymerase II transcription at the level of certain genome sequences. These results are vital to better understand how the splicing reaction can be deregulated in various pathological situations.

Pierre Close adds: 'This mechanism could represent a starting point for the establishment of new therapeutic strategies. Indeed, one of the sub-units of the DBIRD complex, DBC1, is a protein whose expression is widely correlated with cancers such as those of the oesophagus and the breast, and with resistance to chemotherapy treatments. Our future research work will therefore focus on studying the extent to which the regulation of these reactions by DBIRD may influence the development and progression of cancers.'

Source: http://www.nature.com/nature/journal/vaop/ncurrent/full/nature10925.html

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