Werner's syndrome (WS) is a homozygous recessive disease characterized by early onset of many characteristics of normal aging, such as wrinkling of the skin, graying of the hair, cataracts, diabetes, and osteoporosis. Because of the acceleration of aging in WS, the study of this disease will hopefully shed light on the degenerative processes that occur in normal aging. Cells from WS patients grow more slowly and senescence at an earlier population doubling than age-matched normal cells, possibly because these cells appear to lose the telomeric ends of their chromosomes at an accelerated rate. 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 as a means to investigate the dynamic behavior of WRN and the other RecQ helicases. In this regard, we have defined WRN and BLM as DNA damage scanners due to their effective diffusion parameters, whereas other proteins show a pattern of free diffusion and only engage DNA after DNA damage detection has been performed. We are also exploring the role of WRN in the nucleoli and we believe that WRN is recruited to DNA damage either by protein-protein interactions or due to protein post-translational modifications (PMTs). We are exploring the recruitment and retention dynamics of WRN proteins carrying point mutations or with alterations within PMT sites to determine if these elements impact WRNs DNA damage recruitment. Future studies aim to characterize more fully the protein complexes that WRN participates in both before and after double strand DNA damage and other types of DNA damage. Additionally, metabolic alterations are being investigated in multiple WRN-deficient cell types to determine if there are any implications for Wrn loss and metabolisms. Combined these studies are intended to extend our understanding of cellular consequences after loss of WRN function.
| 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 |
| Croteau, Deborah L; Popuri, Venkateswarlu; Opresko, Patricia L et al. (2014) Human RecQ helicases in DNA repair, recombination, and replication. Annu Rev Biochem 83:519-52 |
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