Smc5/6, an atypical SMC complex with two RING-type subunits

Abstract

The Smc5/6 complex plays essential roles in chromosome segregation and repair, by promoting disjunction of sister chromatids. The core of the complex is constituted by an heterodimer of Structural Maintenance of Chromosomes (SMC) proteins that use ATP hydrolysis to dynamically associate with and organize chromosomes. In addition, the Smc5/6 complex contains six non-SMC subunits. Remarkably, and differently to other SMC complexes, the Nse1 and Nse2 subunits contain RING-type domains typically found in E3 ligases, pointing to the capacity to regulate other proteins and complexes through ubiquitin-like modifiers. Nse2 codes for a C-terminal SP-RING domain with SUMO ligase activity, assisting Smc5/6 functions in chromosome segregation through sumoylation of several chromosome-associated proteins. Nse1 codes for a C-terminal NH-RING domain and, although it has been proposed to have ubiquitin ligase activity, no Smc5/6-dependent ubiquitylation target has been described to date. Here, we review the function of the two RING domains of the Smc5/6 complex in the broader context of SMC complexes as global chromosome organizers of the genome.

Nse5/6 is a negative regulator of the ATPase activity of the Smc5/6 complex

“…The precise cellular roles of the Smc5/6 complex remain enigmatic, but mutations within its component proteins have clear and definite impacts on DNA replication and DNA damage repair processes, in particular acting to suppress inappropriate homologous recombination structures that can be formed when replication forks stall or collapse, as well as assisting in resolution of sister chromatids during meiosis [reviewed in refs. [8][9][10][11]. Smc5/6 is also known to be a viral restriction factor for hepatitis B 12,13 , herpes simplex-1 14 and papillomavirus type 31 viruses 15,16 .…”

Nse5/6 is a negative regulator of the ATPase activity of the Smc5/6 complex

“…The precise cellular roles of the Smc5/6 complex remain enigmatic, but mutations within its component proteins have clear and definite impacts on DNA replication and DNA damage repair processes, in particular acting to suppress inappropriate homologous recombination structures that can be formed when replication forks stall or collapse, as well as assisting in resolution of sister chromatids during meiosis [reviewed in ( 8 - 11 )]. Smc5/6 is also known to be a viral restriction factor for hepatitis B ( 12 , 13 ), herpes simplex-1 ( 14 ) and papillomavirus type 31 viruses ( 15 , 16 ).…”

Integrative analysis reveals unique features of the Smc5/6 complex

“…More work will be required to determine structural changes in Smc5/6 during its ATPase cycle and DNA interactions. These future studies will provide further insights into the observed DNA linking and sumoylation activities of the complex (16,(49)(50)(51).…”

“…To test the possibility that the co-evolved Nse2 and Nse5-6 have functional connections, we considered the unique sumoylation function of the Smc5/6 complex that is not shared by other SMCs (16)(17)(18)(19). Nse2 sumoylates Smc5, Smc6, and Nse4, among other substrates, and the sumoylation of Smc5 and 6 contributes to DNA replication and repair (16). However, the functional mechanisms of Nse2 as a SUMO ligase remain to be understood.…”

“…Three Nse subunits, Nse2, Nse5 and Nse6, are not found in any other SMC complexes in either prokaryotes or eukaryotes. Nse2 (aka Mms21) is a SUMO ligase that promotes the sumoylation of more than a dozen genome maintenance factors (16)(17)(18)(19). Nse5 and 6 are thought to act distinctly from Nse2 by forming a subcomplex that recruits the Smc5/6 complex to DNA damage sites (13)(14)(15)(20)(21)(22).…”