In humans there are five RecQ helicases whereas in simpler organisms there is only one. It is of great interest to explore how these proteins function individually and together and whether there is redundancy of helicase function or whether each has unique individual roles. There may be circumstances where they can function in a synergistic manner and this would clarify whether these different RecQ helicases interact with each other and also about the biological importance of certain processes. We and other groups find that the human RecQ helicases participate in DNA repair, and more specifically in certain subpathways of DNA repair. Three of the RecQ helicases are deficient in disorders of segmental premature aging: Werner syndrome, Bloom syndrome and Rothmund Thomson syndrome. Much less is known about the Rothmund-Thomson syndrome protein, RECQL4, and RECQL5, than about the other human RecQ helicases. We find that the RECQL4 protein participates in DNA repair of double and single strand breaks and that cells from individuals with this condition are defective in DNA repair. Using real time imaging, we have shown that RECQL4 is recruited to sites of double strand breaks and that its retention kinetics are different than WRN or BLM. Additionally, we mapped the domain of RECQL4 necessary for DNA damage recruitment. Biochemically, we are characterizing the RECQL4 protein and, while its helicase function is in many ways similar to WRN and BLM helicases, there are also significant differences. We have shown that RECQL4 has a very limited substrate range and that its helicase activity can be seen on short fork DNA substrates but not on long DNA substrates. We are also exploring potential protein interactions and protein complexes that RECQL4 participates in. Previously we showed that RECQL4 could modulate core BER proteins like APE1, pol B;and FEN1. More recently our work has focused on defining the role of RECQL4 after DSB induction and during telomere maintenance. We find that RECQL4 loss increases telomeric sister chromatid exchanges. Furthermore, we discovered that RECQL4 specifically interacts with telomeric proteins. Thus, we are continuing to define and explore the catalytic properties of RECQL4 and potential protein:protein interaction partners especially following DSBs. In collaboration with Dr. Balajee, a prior postdoc here, we reported that RECQL4 is highly elevated in metastatic prostate cancer and may represent a new prostate cancer biomarker. RECQL5 is another member of the RecQ family for which little information is available. We have previously reported that WRN, BLM and RECQL4 can stimulate core base excision repair proteins. Thus we evaluated whether RECQL5 could also stimulate and interact with BER proteins. Indeed, we found that RECQL5 could interact with and stimulate FEN1 incision reactions. We have now expanded the analysis of RECQL5 in BER by performing a microarray analysis and find numerous DNA repair related genes differentially regulated upon RECQL5 loss. Therefore the RecQ helicases not only regulate the activities of BER proteins but they also have the capacity to modify BER gene expression patterns. In addition to RECQL5s role in BER, we are evaluating its role in DSB repair. Like the other RecQ helicases, we find that RECQL5 is recruited to DSBs but its retention kinetics are different than the other RecQ helicases. Additionally, we mapped the domain of RECQL5 that is necessary for DSB recruitment. Thus, in the DSB damage response, it appears that the various RecQ helicases have both complementary and independent roles.
| 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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