The human genome is consistently under attack from exogenous and endogenous genotoxins. DNA double strand breaks (DSBs) are one of the major types of genomic damage that result from this attack. Homologous recombination repair (HRR) and non-homologous end-joining (NHEJ) are the two main pathways repairing DSB in mammalian cells. However, the outcomes are significantly different for NHEJ and HRR. NHEJ generally leads to mutations and genomic rearrangements, whereas conservative HRR usually results in precise repair thus maintains the genetic stability in the event of DNA damage. It is an important matter for the cells to decide which repair pathway to employ at specific DSB sites. Current models suggest that binding of Ku proteins to DNA ends initiates NHEJ whereas binding of RAD52 solicits HRR, and that HRR is more frequently associated with replication or transcriptionally active loci. However, the mechanism that selects HRR to repair a given DSB is not understood.Mammalian RAD52 is involved in the initial stage of homologous recombination. Our recent data show that RAD52 associates with the transcription machinery, and may thereby couple HRR to transcription and provide a mechanism for the cells to select HR over NHEJ at transcriptionally active loci. UBC9 is an essential enzyme in the sumoylation pathway that conjugates the ubiquitin-like protein UBL1/SUMO-1 to certain cellular proteins. UBC9 associates with RAD52 and RAD51. Further data demonstrate that disturbance of UBC9 protein function results in reduced HRR. Our central hypothesis is that mammalian RAD52 plays a role in coupling HRR with transcriptionally active loci, and that UBC9 modulates this process by interacting with RAD52.
Specific aim 1 will test the roles of RAD52 in transcription-associated HRR, and specific aim 2 will further characterize UBC9's role in the regulation of homologous recombination. It has long been known that transcription stimulates homologous recombination. However, the mechanism of this phenomenon is poorly understood. Our studies will provide new insight into the mechanism that couples transcription and homologous recombination in mammalian cells.
| Du, Yuchun; Zhou, Jianhong; Fan, Jinjiang et al. (2009) Streamline proteomic approach for characterizing protein-protein interaction network in a RAD52 protein complex. J Proteome Res 8:2211-7 |
| Rewari, Amar; Lu, Huimei; Parikh, Rahul et al. (2009) BCCIP as a prognostic marker for radiotherapy of laryngeal cancer. Radiother Oncol 90:183-8 |
| Wray, Justin; Liu, Jingmei; Nickoloff, Jac A et al. (2008) Distinct RAD51 associations with RAD52 and BCCIP in response to DNA damage and replication stress. Cancer Res 68:2699-707 |
| Meng, Xiangbing; Yuan, Yuan; Maestas, Adrian et al. (2004) Recovery from DNA damage-induced G2 arrest requires actin-binding protein filamin-A/actin-binding protein 280. J Biol Chem 279:6098-105 |
