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.

SUMO and Transcriptional Regulation: The Lessons of Large-Scale Proteomic, Modifomic and Genomic Studies

“…Finally, SUMOylated proteins can be deSUMOylated and SUMO chains can be depolymerized by SUMO isopeptidases (also known as deSUMOylases) [ 23 , 30 , 31 ]. The deSUMOylases identified so far are SENP-1 to -3, SENP-5 to -7, DeSI-1 and -2 and USPL1.…”

“…Noteworthy SENP-1 shows preference for SUMO-1 whereas the other SENPs preferentially remove SUMO-2/3 [ 23 , 30 , 31 ], but substrate preference displayed by the different SUMO isopeptidases is partly explained by their differential subcellular distribution [ 23 ]. Also of note, SENP6 and -7 are preferentially involved in SUMO chain disassembly [ 30 , 31 ]. Importantly, SUMO is a quite stable protein and can be recycled for further protein modifications.…”

“…Consistently, SUMO has principally been associated with nuclear functions so far, especially at chromatin, as well as in several other nuclear substructures. The characterized nuclear functions of SUMO include, nucleo-cytoplasmic exchanges [ 39 ], the various responses to DNA damages [ 40 , 41 ], mRNA processing and metabolism [ 42 ], chromosome biology and chromatin organization [ 24 , 31 , 43 ] and gene transcription regulation [ 3 , 4 , 24 , 31 , 44 ]. There also exist SUMO-dependent cross-talks between these functions, which are often concurrent, coordinated and sometimes intermingled.…”

“…Moreover, the SUMO proteins themselves an also be subjected to PTMs [ 38 ]. Taken with the fact that the three SUMOs can form chains, which can be branched and which can also involve other members of the ubiquitin family [ 10 , 30 , 31 , 37 ], these observations point to a long underappreciated complexity of the SUMO signal itself. A considerable amount of work is still needed to fully characterize it biochemically and functionally, including for better understanding of transcriptional control in cells.…”

Microarray screening reveals a non-conventional SUMO-binding mode linked to DNA repair by non-homologous end-joining

“…These findings underpin the validity of our approach in identifying receptors in pathways associated with known SUMO functions, and indeed in contexts triggering the formation of polySUMO chains, an achievement previously unattained with proteome microarrays 55 . Other significantly enriched ontologies included chromatin-associated processes such as remodelling and nucleosome assembly/disassembly that are also linked to SUMO function 3,56 (Fig. 1C).…”