SMC complexes and topoisomerase II work together so that sister chromatids can work apart

Abstract

T he pairing of sister chromatids in interphase facilitates error-free homologous recombination (HR). Sister chromatids are held together by cohesin, one of three Structural Maintenance of Chromosomes (SMC) complexes. In mitosis, chromosome condensation is controlled by another SMC complex, condensin, and the type II topoisomerase (Top2). In prophase, cohesin is stripped from chromosome arms, but remains at centromeres until anaphase, whereupon it is removed via proteolytic cleavage by separase. The third SMC complex, Smc5/6, is generally described as a regulator of HR-mediated DNA repair. However, cohesin and condensin are also required for DNA repair, and HR genes are not essential for cell viability, but the SMC complexes are. Smc5/6 null mutants die in mitosis, and in fission yeast, Smc5/6 hypomorphs show lethal mitoses following genotoxic stress, or when combined with a Top2 mutant, top2-191. We found these mitotic defects are due to retention of cohesin on chromosome arms. We also show that Top2 functions in the cohesin cycle, and accumulating data suggests this is not related to its decatenation activity. Thus the SMC complexes and Top2 functionally interact, and any DNA repair function ascribed to Smc5/6 is likely a reflection of a more fundamental role in the regulation of chromosome structure.

Genome-wide and protein kinase-focused RNAi screens reveal conserved and novel damage response pathways in Trypanosoma brucei

“…Perhaps SMC5/6 functions are assumed by the two putative nuclear T . brucei Topoisomerase II isoforms [76–78](S2 Table). A further T .…”

Dynamic localization of SMC5/6 complex proteins during mammalian meiosis and mitosis implies functions in distinct chromosome processes

“…Moreover, evidence suggests a close relationship between SMC5/6 and cohesin complexes in unperturbed cells, where both complexes require the participation of Scc2 to load on the chromosomes during interphase (Lindroos et al, 2006), and, in addition, the SMC5/6 subunit NSE2 sumoylates the cohesin subunits RAD21/Scc1, Smc1 and Smc3 in human and budding yeast cells (Takahashi et al, 2008;McAleenan et al, 2012;. SMC5/6 complexes seem to be functionally related to Topo IIa in the resolution of topological stress during replication (Tapia-Alveal et al, 2010;Kegel and Sjögren, 2011). In fact, the fission yeast smc6-74 mutant is synthetically lethal with temperature-sensitive top2-191 at semipermissive temperatures (Verkade et al, 1999), and budding yeast nse2 and smc6-56 mutants show synthetic growth defects when combined with mutations in Top2 (Takahashi et al, 2008).…”

Incision of damaged DNA in the presence of an impaired Smc5/6 complex imperils genome stability

“…whether ahead of or behind the replisome. The authors favour the former possibility as depicted in this model for there are functional interactions between Smc5/6 complex and Topoisomerase II, which serves to relieve torsional stress ahead of the replication fork (41,92). …”