Cooperativity of the SUMO and Ubiquitin Pathways in Genome Stability

Abstract

Covalent attachment of ubiquitin (Ub) or SUMO to DNA repair proteins plays critical roles in maintaining genome stability. These structurally related polypeptides can be viewed as distinct road signs, with each being read by specific protein interaction motifs. Therefore, via their interactions with selective readers in the proteome, ubiquitin and SUMO can elicit distinct cellular responses, such as directing DNA lesions into different repair pathways. On the other hand, through the action of the SUMO-targeted ubiquitin ligase (STUbL) family proteins, ubiquitin and SUMO can cooperate in the form of a hybrid signal. These mixed SUMO-ubiquitin chains recruit “effector” proteins such as the AAA+ ATPase Cdc48/p97-Ufd1-Npl4 complex that contain both ubiquitin and SUMO interaction motifs. This review will summarize recent key findings on collaborative and distinct roles that ubiquitin and SUMO play in orchestrating DNA damage responses.

SUMO-Mediated Regulation of Nuclear Functions and Signaling Processes

“…For example, SUMO1 modification of BRCA1 can increase its ubiquitin E3 activity, while similar modification of HERC2 favors the formation of ubiquitin E2-E3 complexes composed of RNF8 and UBC13 (Danielsen et al, 2012; Morris et al, 2009). The combined effects of sumoylation and ubiquitination in these situations generally help recruit DNA repair factors and enhance their functions, but may also enable disassembly of repair complexes through STUbL or the Cdc48 segregase (Nie and Boddy, 2016; Schwertman et al, 2016). Sumoylation also regulates ubiquitination enzymes in other cellular contexts.…”

Ubiquitin-dependent and independent roles of SUMO in proteostasis

“…However, RNF4 prefers to target proteins that are modified by SUMO chains of at least three SUMO moieties (118). RNF4 regulates substrates involved in a multitude of pathways, including kinetochore assembly (87), cell survival upon hypoxic stress (125), mitogen-activated protein (MAP) kinase signaling (39), transcriptional responses to heat shock (82), ion transport (2), and the DNA damage response (91). The most extensively studied substrate of RNF4 is the promyelocytic leukemia protein (PML).…”

SUMO conjugation – a mechanistic view

“…SUMO belongs to the superfamily of ubiquitin-like (Ubl) modifiers and performs essential functions in most organisms. Sumoylation is involved in a large variety of fundamental cellular processes, including DNA replication, transcription, cell cycle regulation, DNA damage repair, chromatin organization, ribosome biogenesis, pre-mRNA splicing, nuclear trafficking, signal transduction and protein degradation (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). Such a plethora of functions implies the existence of multiple targets.…”

“…Such stress stimuli include DNA damage, heat shock, proteasomal inhibition, viral infection or ischemic challenge. These significant rearrangements in the SUMO proteome appear to represent a versatile immediate stress response, required, for example, for DNA damage repair (2,7,18) or to protect the brain against focal cerebral ischemic damage (19). However, constitutively increased sumoylation has rather negative effects and correlates with resistance to cancer treatments, increased tumor metastasis and relapse (20)(21)(22)(23)(24).…”