Abstract
Despite the continued analysis of HDAC inhibitors in clinical trials, the heterogeneous nature of the protein complexes they target limits our understanding of the beneficial and off-target effects associated with their application. Among the many HDAC protein complexes found within the cell, Sin3 complexes are conserved from yeast to humans and likely play important roles as regulators of transcriptional activity. The presence of two Sin3 paralogs in humans, SIN3A and SIN3B, may result in a heterogeneous population of Sin3 complexes and contributes to our poor understanding of the functional attributes of these complexes. Here, we profile the interaction networks of SIN3A and SIN3B to gain insight into complex composition and organization. In accordance with existing data, we show that Sin3 paralog identity influences complex composition. Additionally, chemical cross-linking MS identifies domains that mediate interactions between Sin3 proteins and binding partners. The characterization of rare SIN3B proteoforms provides additional evidence for the existence of conserved and divergent elements within human Sin3 proteins. Together, these findings shed light on both the shared and divergent properties of human Sin3 proteins and highlight the heterogeneous nature of the complexes they organize.
Highlights
Complex subunit homology to yeast Sin3 complex components may assist in defining distinct forms of the Sin3 complex in humans
SIN3A and SIN3B isoform 2 (SIN3B_2) enriched the same number of proteins, only 7 proteins were enriched in both SIN3A and SIN3B_2 purifications (Fig. 1E)
Among proteins enriched by both SIN3A and SIN3B_2 were HDAC1/HDAC2 and RBBP4/RBBP7, proteins with homology to the yeast Sin3 core complex components Rpd3 and Ume1, respectively
Summary
Complex subunit homology to yeast Sin complex components may assist in defining distinct forms of the Sin complex in humans. The presence of two Sin paralogs in humans, SIN3A and SIN3B, may result in a heterogeneous population of Sin complexes and contributes to our poor understanding of the functional attributes of these complexes. The characterization of rare SIN3B proteoforms provides additional evidence for the existence of conserved and divergent elements within human Sin proteins. Together, these findings shed light on both the shared and divergent properties of human Sin proteins and highlight the heterogeneous nature of the complexes they organize. In higher eukaryotes, the presence of additional components not found in lower eukaryotic forms of the Sin complexes likely increases the diversity of complex functions Contributing to this expansion of components is the acquisition of paralogous genes encoding Sin proteins. That SIN3A and SIN3B cannot compensate for the loss of one another provides evidence for paralog-specific functions within mammals and suggests that variations within the Sin complexes have functional consequences
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