DNA damage accumulates during life and is thought to contribute to aging and genomic instability. Therefore, defining those proteins and pathways that maintain genomic instability may be critical in preventing aging and age-related degeneration. This project aims to understand what roles the five human RecQ helicases play in DNA repair and genomic stability. We and other groups find that the human RecQ helicases participate in DNA repair, and more specifically in certain sub pathways of DNA repair. Mutations in RECQL4 are associated with three diseases Rothmund Thomson, RAPADILINO and Baller-Gerold syndrome while WRN and BLM mutations are associated with Werner and Bloom syndrome, respectively. We have recently shown in human fibroblasts that senescence is induced upon knockdown of the three disease-associated RecQ helicases RECQL4, WRN and BLM. These findings were further extended to a mouse model of Recql4 in which we also observed elevated senescence in bone marrow and other tissues. Senescence was associated with elevated endogenous DNA damage and activation of DNA damage checkpoint proteins. Together our results suggest that elevated senescence as a result of loss of RECQL4, WRN and BLM is due to enhanced endogenous DNA damage. One major goal of our lab is to delineate the unique and complementary roles of the human RecQ helicases, with the expectation that we might fully explain each proteins function. Each RecQ possesses helicase and strand annealing activity as well as domains that confer unique functionality. RECQL1 was evaluated for its role at telomeres because it appears BLM, WRN and RECQL4 each may function here. As expected, loss of RECQL1 does indeed cause telomere dysfunction. Therefore, it appears that several of the RecQ helicases contribute to telomere integrity and that there may be some functional redundancy. We've demonstrated that all the RecQ helicases can be recruited to laser-induced double strand breaks, however the details of how each RecQ participates in DSB is less clear. Recently, we showed that RECQL4 interacts with Ku and further that loss of RECQL4 alters in vivo DSB repair efficiency. This expands the list of RecQs that interact with Ku to three, WRN, RECQL1 and RECQL4. Further dissection of the role of RecQ proteins in DSB repair is ongoing. RECQL5 is another member of the RecQ family for which little information is available. Loss of RECQL5 leads to increased endogenous DNA damage. Previously we investigated RECQL5s recruitment and retention to oxidative DNA damage and more recently we evaluated its role in DNA interstrand crosslinkrepair. Like the other RecQ helicases, we find that RECQL5 is recruited to DNA interstrand crosslinks. Additionally, we mapped the domain of RECQL5 that is necessary for this recruitment. Thus, like WRN and BLM, RECQL5 is recruited to psoralen-induced DNA damage and it likely plays a role in its repair. Therefore, RECQL5 appears to play a backup role in DNA interstrand crosslink repair. Our lab, in collaboration with others, continues to identify and characterize potential RecQ inhibitors. Thus far, both inhibitors for both WRN and BLM have been identified, however both are suboptimal, and thus we are continuing to screen for more optimized inhibitors.
| Lu, Huiming; Shamanna, Raghavendra A; de Freitas, Jessica K et al. (2017) Cell cycle-dependent phosphorylation regulates RECQL4 pathway choice and ubiquitination in DNA double-strand break repair. Nat Commun 8:2039 |
| Lu, Huiming; Shamanna, Raghavendra A; Keijzers, Guido et al. (2016) RECQL4 Promotes DNA End Resection in Repair of DNA Double-Strand Breaks. Cell Rep 16:161-173 |
| Arora, Arvind; Abdel-Fatah, Tarek M A; Agarwal, Devika et al. (2016) Clinicopathological and prognostic significance of RECQL5 helicase expression in breast cancers. Carcinogenesis 37:63-71 |
| Arora, Arvind; Agarwal, Devika; Abdel-Fatah, Tarek Ma et al. (2016) RECQL4 helicase has oncogenic potential in sporadic breast cancers. J Pathol 238:495-501 |
| Shamanna, Raghavendra A; Lu, Huiming; de Freitas, Jessica K et al. (2016) WRN regulates pathway choice between classical and alternative non-homologous end joining. Nat Commun 7:13785 |
| 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 |
| Sarkar, Jaya; Wan, Bingbing; Yin, Jinhu et al. (2015) SLX4 contributes to telomere preservation and regulated processing of telomeric joint molecule intermediates. Nucleic Acids Res 43:5912-23 |
| 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 |
| Bürkle, Alexander; Grune, Tilman; Gonos, Efstathios S et al. (2015) Editorial. Mech Ageing Dev 151:1 |
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