Cooperativity of the SUMO and Ubiquitin Pathways in Genome Stability.

Minghua Nie,Michael Boddy

doi:10.3390/biom6010014

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.

Highlights

The integrity of the cell’s genome is under constant threat from various external and internal genotoxic agents, such as UV and oxidative stress
Given the apparently pivotal role played by SUMO2/3 chains in the DNA damage response (DDR), it appears likely that ZNF451 activity will impact DNA repair
There are a number of excellent recent reviews covering many of the E3 ubiquitin ligases that are recruited to chromatin/DNA (e.g., [4,10]), so here we focus largely on the recruitment mechanisms and functions of the SUMO-targeted ubiquitin ligase (STUbL) family

Summary

Introduction

The integrity of the cell’s genome is under constant threat from various external and internal genotoxic agents, such as UV and oxidative stress. Two structurally related small protein modifiers, ubiquitin and SUMO, are conjugated to target proteins via a similar cascade of biochemical reactions Both SUMO and ubiquitin play important, often interconnected, and even interdependent roles in DNA damage repair. Slx5-Slx, and fission yeast Rfp1/2-Slx heterodimers, can direct SUMO conjugates for degradation at the proteasome [13,14,15,16,17] In this mechanism, a tandem array of SUMO interaction motifs (SIMs) in STUbLs enables them to selectively ubiquitylate target proteins that are modified by polymeric SUMO chains (Figure 1). Chain to produce ubiquitin-SUMO hybrid chains, a signal that is “read” by proteins containing both a ubiquitin interacting motif (UIM) and a SIM These hybrid chains can either recruit additional repair factors, or promote protein extraction from complexes/chromatin through the activity of the AAA+. Crosstalk between the SUMO and ubiquitin pathways has been demonstrated on Top, ID complex, Rad, and XPC extraction

DNA Damage-Induced Recruitment of SUMO and Ubiquitin E3 Ligases

Potential New SUMO E3 Ligases in DNA Repair

SUMO Mimicry Integrates SUMO and Ubiquitin Signaling in DNA Repair

Recruitment Mechanisms and Functions of STUbL on Chromatin

Coordinated and Distinct Roles of Ubiquitin and SUMO in DNA Repair

Conclusions and Future Directions