The Smc complexes in DNA damage response

The highly conserved structural maintenance of chromosomes (Smc) proteins regulate chromosome architecture and organization from bacteria to human. Most prokaryotes have a single Smc protein which forms a homodimer, while there are at least six Smc family members, Smc1-6, that form three heterodimers in eukaryotic organisms [1] (Figure 1). Smc1 and Smc3 form the core of the cohesin complex which maintains sister-chromatid cohesion during mitosis to ensure accurate chromosome segregation [2]. Smc2 and Smc4 constitute the condensin complexes that promote chromosome condensation [3]. Smc5 and Smc6 form a complex that plays critical roles in DNA repair [4,5].The Smc proteins contain about 1,000 amino acids and share similar domain structures. The ATPase domain of each Smc protein is separated into N- and C-terminal halves by a long linker. The two nucleotide-binding Walker A and Walker B motifs reside in the two different ATPase halves. The Smc linker folds into an intramolecular antiparallel coiled coil and allows the N-terminal ATPase half of an Smc protein to fold back to its C-terminal ATPase half and create a single globular ATPase head (Figure 1). The hinge domain at one end of the coiled coil mediates the heterodimerization of eukaryotic Smc proteins [1,6,7]. The two ATPase heads at the other end of the coiled coil can transiently interact with each other to bind and hydrolyze ATP. As revealed by electron microscopy, the Smc heterodimers can adopt different conformations, including V-shaped dimer and ring-like structures, possibly depending on the nucleotide-binding states of their ATPase heads [8,9]. Each Smc heterodimer associates with non-Smc subunits to form functional Smc complexes.The genomic DNA with a cell experiences many types of damage daily. These damages can result from exogenous factors, such as ultraviolet (UV) radiation, ionizing radiation (IR), and chemical carcinogens, or from endogenous factors, such as stalled replication forks due to replicat