The Smc complexes in DNA damage response

Abstract

The structural maintenance of chromosomes (Smc) proteins regulate nearly all aspects of chromosome biology and are critical for genomic stability. In eukaryotes, six Smc proteins form three heterodimers--Smc1/3, Smc2/4, and Smc5/6--which together with non-Smc proteins form cohesin, condensin, and the Smc5/6 complex, respectively. Cohesin is required for proper chromosome segregation. It establishes and maintains sister-chromatid cohesion until all sister chromatids achieve bipolar attachment to the mitotic spindle. Condensin mediates chromosome condensation during mitosis. The Smc5/6 complex has multiple roles in DNA repair. In addition to their major functions in chromosome cohesion and condensation, cohesin and condensin also participate in the cellular DNA damage response. Here we review recent progress on the functions of all three Smc complexes in DNA repair and their cell cycle regulation by posttranslational modifications, such as acetylation, phosphorylation, and sumoylation. An in-depth understanding of the mechanisms by which these complexes promote DNA repair and genomic stability may help us to uncover the molecular basis of genomic instability in human cancers and devise ways that exploit this instability to treat cancers.

Figure 1

Architecture of the Smc complexes. (A) The core of each Smc complex is formed by two Smc proteins. Each Smc protein contains an ATPase head domain, a hinge domain, and an intramolecular antiparallel coiled coil that connects the two. The hinge domain mediates the dimerization of Smc proteins. (B) Various Smc complexes found in bacteria and eukaryotes. Each Smc complex is composed of a specific Smc dimer and several non-Smc subunits. (i) The bacterial Smc complex from Bacillus subtilis. ScpA connects the two ATPase heads of the Smc homodimer. (ii) The Smc1/3 cohesin complex. (iii) The Smc5/6 complex. (iv) The condensin I complex. H, D2, and G stand for CAP-H, CAP-D2, and CAP-G, respectively. (v) The condensin II complex. H2, D3, and G2 stand for CAP-H2, CAP-D3, and CAP-G2, respectively. (vi) The condensin-like dosage compensation complex in C. elegans. DPY-27 is an Smc4 variant.

Figure 2

Functions of cohesin in DNA damage response during the cell cycle. The function of cohesin in promoting DSB repair through sister-chromatid homologous recombination (HR) has been established in multiple organisms ranging from yeast to man. Most of the other proposed functions are only demonstrated in specific organisms, and their evolutionary conservation needs to be further tested.

Figure 3

Functions of the Smc5/6 complex in DNA repair and rDNA maintenance. See text for details.