Emerging roles for the human condensin complexes in cellular DNA repair

In human cells, chromatin structure changes dramatically upon entry into mitosis. Such changes are the result of a well-orchestrated interplay of many factors including the structural maintenance of chromosomes (SMC) family of proteins. The SMC proteins are a highly conserved group of factors shown to be essential for proper mitotic chromosome condensation and segregation. SMC proteins form the core of several multi-protein complexes which participate in mitotic chromosome condensation, sister chromatid cohesion, and other aspects of chromosome dynamics. Condensin I is one of the major SMC containing complexes and is required for proper mitotic chromosome organization. Condensin I is made up of the hCAP-E/hCAP-C SMC heterodimer and three non-SMC subunits, CNAP1 (hCAP-D2/Eg7), hCAP-G and hCAP-H. These non-SMC subunits are important for the association of condensin I with chromatin and most likely regulate the functional specificity of the condensin I complex. However, the exact role performed by each subunit is poorly understood. Our laboratory previously identified a nuclear localization and c hromosome targeting domain (NCTD) contained within the carboxy-terminus of the CNAP1 protein. The NCTD is required for the binding of CNAP1 to mitotic chromosomes, and possibly targeting holo-condensin I onto mitotic chromatin. To further understand how the CNAP1-NCTD is regulated, we used farwestern analysis to screen for proteins which interact with this functional domain. Results from this analysis revealed the carboxy-terminus of CNAP1 interacted with several nuclear proteins with high specificity, including the DNA repair enzyme poly(ADP-ribose) polymerase I (PARP-1) and CENP-C. An interaction between PARP-1 and holo-condensin I complex was later confirmed in vivo. Interestingly, this interaction is highly induced in response to DNA damage. We also show that condensin I interacts with not only PARP-1, but a specific subset of base excision repair factors including XRCC1, FEN-1 and DNA polymerases delta/&egr; following DNA damage. A significant increase is the amount of condensin I bound to chromatin after oxidative stress was also observed, suggesting recruitment of the complex to DNA damage sites. This was confirmed using a UVA 337 nm laser which generates several types of damage including base damage. The recruitment of condensin I to UVA laser induced DNA damage sites further supports a role for condensins in DNA repair. Finally, we show that depletion of condensin subunits results in compromised single-strand break repair efficiency. Taken together, these results suggest a role for condensin I in single-strand break repair in higher eukaryotes.