Investigation of the Sin3a-HDAC1-SDS3 transcriptional co-repressor complex
Year: 2015
Type: dissertation
Abstract: The transcriptional co-repressor Sin3a is a ubiquitous eukaryotic protein complex\nthat has a multitude of critical functions, including the regulation of embryonic\ndevelopment, cell division and maintenance of genomic integrity. It incorporates\nthe highly related HDAC1 and HDAC2 enzymes as its catalytic subunits, which\ninteract with the complex through the HID domain of the Sin3a co-repressor.\nSin3a is responsible for deacetylating lysines of Histone tails, condensing\nchromatin and consequently repressing the transcription of genes. The enzymatic\nactivities of HDAC1 and 2 within Sin3a depend on the association of the Sin3aspecific\nSDS3 protein, which also interacts with the complex via the HID domain.\nThe mechanism by which Sin3a recruits HDAC1, HDAC2 and SDS3 remains\nunknown, and elucidating it would represent a big step forward in understanding\nthe epigenetic regulation of genes through the deacetylation of chromatin.\nThe aim of this thesis is to understand how Sin3a recruits its catalytic subunits in\nto the complex as well as to get a deeper insight into the role of SDS3 in the HID\ndomain by using both structural (X-ray crystallography) and biochemical\napproaches.\nOur data suggests that HDAC1 may interact with Sin3a through an extended\nsurface of the co-repressor and that SDS3 stabilizes this interaction by\nsimultaneously binding to HDAC1 and Sin3a. Enzymatic and kinetic assays\nindicate that Sin3a may be the only Class I HDAC containing complex that is not\nregulated by IP4. IP4 is a co-factor that regulates the activity of the Class I HDACdependent\ncomplexes NuRD and SMRT-NCoR. Thus, our results suggest that\nSin3a may have followed a separate evolutionary pattern and its activity may be\nregulated in a different way.
Source: Figshare
Author: Nicola Portolano
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W315085103