In general, WS cells have a high level of genomic instability, with increased amounts of DNA deletions, insertions, and rearrangements. These effects could potentially be the result of defects in DNA repair, replication, and/or recombination, although the actual biochemical defect remains unknown. We are comparing WRN to the other RecQ helicases. There are five human RecQ proteins and all are involved in the maintenance of genome stability. We are especially interested in defining the unique and shared roles of WRN and the other RecQ helicases in double strand break repair. Confocal microscopy is used to investigate the dynamic behavior of WRN and its interacting partners. There are multiple pathways whereby a cell can repair a double strand break (DSB) and recently we investigated WRN's role in DSB repair pathway choice (Homologous Recombination (HR) vs classical Non-Homologous End Joining (c-NHEJ) vs Alternative NHEJ (alt-NHEJ)). We find that WRN regulates resection at the 5' ends of DSBs, and influences the choice between c-NHEJ and alt-NHEJ. In mouse cells lacking Wrn and Trf2, we found that alt-NHEJ is favored leading to an increased frequency of telomere fusions. Thus, alt-NHEJ may be driving genomic instability in WRN-deficient cells. The implications from this work are that small molecule inhibitors of alt-NHEJ may have therapeutic benefit in WRN-deficient cells by preventing genomic rearrangements and genome stability.
| Maity, Jyotirindra; Das, Biswadip; Bohr, Vilhelm A et al. (2018) Acidic domain of WRNp is critical for autophagy and up-regulates age associated proteins. DNA Repair (Amst) 68:1-11 |
| Lee, Mina; Shin, Soochul; Uhm, Heesoo et al. (2018) Multiple RPAs make WRN syndrome protein a superhelicase. Nucleic Acids Res 46:4689-4698 |
| Shamanna, Raghavendra A; Croteau, Deborah L; Lee, Jong-Hyuk et al. (2017) Recent Advances in Understanding Werner Syndrome. F1000Res 6:1779 |
| Shin, Soochul; Lee, Jinwoo; Yoo, Sangwoon et al. (2016) Active Control of Repetitive Structural Transitions between Replication Forks and Holliday Junctions by Werner Syndrome Helicase. Structure 24:1292-1300 |
| Tippana, Ramreddy; Hwang, Helen; Opresko, Patricia L et al. (2016) Single-molecule imaging reveals a common mechanism shared by G-quadruplex-resolving helicases. Proc Natl Acad Sci U S A 113:8448-53 |
| Shamanna, Raghavendra A; Lu, Huiming; Croteau, Deborah L et al. (2016) Camptothecin targets WRN protein: mechanism and relevance in clinical breast cancer. Oncotarget 7:13269-84 |
| Khadka, Prabhat; Croteau, Deborah L; Bohr, Vilhelm A (2016) RECQL5 has unique strand annealing properties relative to the other human RecQ helicase proteins. DNA Repair (Amst) 37:53-66 |
| Khadka, Prabhat; Hsu, Joseph K; Veith, Sebastian et al. (2015) Differential and Concordant Roles for Poly(ADP-Ribose) Polymerase 1 and Poly(ADP-Ribose) in Regulating WRN and RECQL5 Activities. Mol Cell Biol 35:3974-89 |
| Edwards, Deanna N; Machwe, Amrita; Chen, Li et al. (2015) The DNA structure and sequence preferences of WRN underlie its function in telomeric recombination events. Nat Commun 6:8331 |
| Keijzers, Guido; Maynard, Scott; Shamanna, Raghavendra A et al. (2014) The role of RecQ helicases in non-homologous end-joining. Crit Rev Biochem Mol Biol 49:463-72 |
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