The human body is constantly exposed to environmental stresses that induce DNA damage/mutations. Such damage must be properly recognized and repaired in order to maintain genome integrity. Accumulation of DNA damage is associated with sporadic cancers, developmental abnormalities, and aging. Frequent identification of mutations in DNA repair genes in cancers and heritable diseases highlight the critical significance of the DNA damage response/repair process. Thus, understanding the underlying mechanisms is important to the environmental health sciences for assessment of the body's reactions to the environmental insults. Condensin is an essential multiprotein complex that organizes higher order chromatin structure and is involved in mitotic chromosome condensation. Although the precise mechanism of the in vivo condensation process is not well understood, condensin appears to mediate condensation by physically interacting with chromosomes during mitosis. Interestingly, a subpopulation of condensin also associates with interphase chromatin, although its role is not clear. Recently, we have obtained evidence that human condensin interacts in a S/G2 phase-specific manner with poly(ADP-ribose)polymerase-1 (PARP-1), a factor known to be involved in DNA damage recognition/repair and maintenance of genome integrity. Interestingly, the interaction between condensin and PARP-1 is highly enhanced and stabilized upon induction of DNA damage. Furthermore, by chromatin crosslinking and immunoprecipitation (CHIP) of restriction enzyme-induced DNA breaks, we found that condensin is recruited to DNA damage sites in vivo. Based on these results, the objective of this project is :o test the novel hypothesis that condensin plays a role in DNA repair together with PARP-1 by being recruited :o the damage site and modulating local chromatin structure at the damage sites.
Specific aims are 1) biochemical dissection of condensin's interaction with PARP-1, 2) functional analysis of condensin's role in DNA damage response/repair using an RNAi approach and mutant cells, and 3) analysis of in vivo condensin recruitment to DNA breaks induced by endonucleases. The proposed project will address the new role of a nigher order chromatin remodeling factor in DNA damage recognition/response, and provide a novel insight into the chromatin structural changes that occur during the DNA damage response. I believe that the project will make a significant contribution to our understanding of genome maintenance in human cells.
| Kong, Xiangduo; Stephens, Jared; Ball Jr, Alexander R et al. (2011) Condensin I recruitment to base damage-enriched DNA lesions is modulated by PARP1. PLoS One 6:e23548 |
| Heale, Jason T; Ball Jr, Alexander R; Schmiesing, John A et al. (2006) Condensin I interacts with the PARP-1-XRCC1 complex and functions in DNA single-strand break repair. Mol Cell 21:837-48 |
