SUMO: a multifaceted modifier of chromatin structure and function

Abstract

A major challenge in nuclear organization is the packaging of DNA into dynamic chromatin structures that can respond to changes in the transcriptional requirements of the cell. Posttranslational protein modifications, of histones and other chromatin-associated factors, are essential regulators of chromatin dynamics. In this Review, we summarize studies demonstrating that posttranslational modification of proteins by small ubiquitin-related modifiers (SUMOs) regulates chromatin structure and function at multiple levels and through a variety of mechanisms to influence gene expression and maintain genome integrity.

Figure 1. The SUMO pathway and molecular consequences of sumoylation

(A) SUMO is synthesized as a precursor, processed to a mature form by SUMO-specific isopeptidases and covalently conjugated to protein substrates via an E1, E2 and E3 enzyme cascade. Sumoylated protein substrates are demodified by SUMO-specific isopeptidases. (B) The molecular consequences of sumoylation (S) include protein targeting, alteration of protein or enzyme function, effects on protein stability, and effects on protein-protein interactions. Sumoylation can promote or antagonize protein stability by either blocking ubiquitylation of lysine residues or by promoting ubiquitylation (Ub) upon recognition by SUMO-targeted ubiquitin ligases (STUbL). Effects on protein-protein interactions may be modulated at multiple levels, including polymeric chain formation and intersection with other posttranslational modifications such as phosphorylation (P).

Figure 2. Sumoylation functions as an activator and a repressor of gene expression

(A) Sumoylation represses gene expression by promoting DNA methylation (yellow dots) through DNMT1 activation. (B) Sumoylation represses gene expression by facilitating assembly of repressive complexes on methylated DNA and at promoters. Sumoylation also inhibits the activities of transcription factors (TFs) and affects HDAC recruitment and function. (C) Sumoylation promotes the assembly of repressive PcG bodies. (D) Sumoylation promotes DNA demethylation and gene activation through mechanisms involving the SUMO-targeted ubiquitin E3 ligase activity of RNF4. (E) Sumoylation facilitates the assembly of complexes on chromatin that promote transcription. (F) Sumoylation positively influences RNA polymerase II (RNA Pol II) recruitment to constitutively active gene promoters.

Figure 3. Sumoylation maintains genome integrity at repetitive DNA domains

(A) Sumoylation limits telomere elongation by regulating interactions between Cdc13 and Stn1. (B) Sumoylation of unknown proteins affects sub-telomeric chromatin structure. (C) Sumoylation promotes the assembly of ALT PML nuclear bodies (APBs) essential for telomere maintenance in telomerase-deficient cells. (D) Sumoylation of Rad52 promotes the movement of DNA double-strand breaks from intranucleolar domains to the nucleolar periphery for optimal repair. (E) Sumoylation of HP1α regulates its association with α-satellite RNA and recruitment to centromeres. (F) Sumoylation functions to resolve DNA replication and repair intermediates within repetitive DNA domains and to promote decatenation.