Functions of the proteasome on chromatin

Abstract

The proteasome is a large self-compartmentalized protease complex that recognizes, unfolds, and destroys ubiquitylated substrates. Proteasome activities are required for a host of cellular functions, and it has become clear in recent years that one set of critical actions of the proteasome occur on chromatin. In this review, we discuss some of the ways in which proteasomes directly regulate the structure and function of chromatin and chromatin regulatory proteins, and how this influences gene transcription. We discuss lingering controversies in the field, the relative importance of proteolytic versus non-proteolytic proteasome activities in this process, and highlight areas that require further investigation. Our intention is to show that proteasomes are involved in major steps controlling the expression of the genetic information, that proteasomes use both proteolytic mechanisms and ATP-dependent protein remodeling to accomplish this task, and that much is yet to be learned about the full spectrum of ways that proteasomes influence the genome.

Figure 1

Localization of proteasomes on chromosomes. The cartoon shows an idealized eukaryotic chromosome, depicting the centromere (“CEN”) a pol II-transcribed gene, a tRNA gene, a site of DNA damage, a site of cryptic transcription (“cryptic txn”) and a telomere. Above the cartoon, symbolized with red bars, are regions shown to be bound by one or more proteasome subunits.

Figure 2

Models for recruitment of proteasome subunits to chromatin. (a) Recruitment by direct contact with activators. A model activator, with its separable DNA-binding domain (DBD) and transcriptional activation domain (TAD) is shown bound to an upstream activating sequence (UAS) at a yeast promoter. In this model, direct contact between the TAD of the activator and one or more ATPases in the 19S base complex leads to promoter-selective recruitment of 19S base components to chromatin; (b) Recruitment by intermediary proteins. In this model, binding of an adapter complex (consisting of Cks1 and Cdk1) to histone H4 (brown circle) tails leads to recruitment of 19S proteasome components; (c) Recruitment by ubiquitylated substrates. In this model, we propose that the presence of one or more ubiquitylated substrates on chromatin recruits proteasomes. “CA” stands for co-activator. Note that this model is consistent with canonical views of how the proteasome is recruited into other biological processes, but the specific ubiquitylated proteins here are arbitrary.

Figure 3

Functions of the proteasome in pol II-mediated transcription. The cartoon shows an idealized mRNA-type gene, with steps shown to be influenced by proteasome function numbered in grey circles 1–5. 1: Controlling the dynamics of activator binding; 2: Controlling co-activator recruitment; 3: Promoting transcriptional elongation; 4: Histone eviction ahead of traveling pol II; 5: Transcription termination.