SUMO Chains Rule on Chromatin Occupancy

Abstract

The dynamic and reversible post-translational modification of proteins and protein complexes with the ubiquitin-related SUMO modifier regulates a wide variety of nuclear functions, such as transcription, replication and DNA repair. SUMO can be attached as a monomer to its targets, but can also form polymeric SUMO chains. While monoSUMOylation is generally involved in the assembly of protein complexes, multi- or polySUMOylation may have very different consequences. The evolutionary conserved paradigmatic signaling process initiated by multi- or polySUMOylation is the SUMO-targeted Ubiquitin ligase (StUbL) pathway, where the presence of multiple SUMO moieties primes ubiquitylation by the mammalian E3 ubiquitin ligases RNF4 or RNF111, or the yeast Slx5/8 heterodimer. The mammalian SUMO chain-specific isopeptidases SENP6 or SENP7, or yeast Ulp2, counterbalance chain formation thereby limiting StUbL activity. Many facets of SUMO chain signaling are still incompletely understood, mainly because only a limited number of polySUMOylated substrates have been identified. Here we summarize recent work that revealed a highly interconnected network of candidate polySUMO modified proteins functioning in DNA damage response and chromatin organization. Based on these datasets and published work on distinct polySUMO-regulated processes we discuss overarching concepts in SUMO chain function. We propose an evolutionary conserved role of polySUMOylation in orchestrating chromatin dynamics and genome stability networks by balancing chromatin-residency of protein complexes. This concept will be exemplified in processes, such as centromere/kinetochore organization, sister chromatid cohesion, DNA repair and replication.

Keywords: PolySUMOylation; RNF4; SENP6; SUMO chains; StUbL.

FIGURE 1

A network of SENP6 targets identified by two recent unbiased proteomic studies (Liebelt et al., 2019; Wagner et al., 2019). Candidate SENP6 targets identified in both studies were combined into a single dataset. This dataset was then used for the generation of a network using the STRING database (version 11.0, https://string-db.org). Only highest confidence interactions (interaction score > 0.9) were considered. Experiments and databases were used as interaction sources. Disconnected nodes were removed from the network. The network data was imported into Cytoscape. The core components of the constitutive centromere associated network (CCAN) are highlighted as red subcluster. The associated CENP-B and the CENP-A targeting factors Mis18A/Mis18BP1 are depicted in light red and yellow, respectively. The cohesion complex is represented by the green subcluster (with the CTCF targeting factor in light green) and the SMC5/6 complex is highlighted in magenta. The SMC5/6 recruitment factor FAM178A/Slf2 is shown in pink.

FIGURE 2

Balancing SUMO chain formation controls chromatin residency of the cohesion complex (A), the centromere network (B) and the FA repair pathway (C). For details see text.