DNA damage accumulates during life and is thought to contribute to the 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 subpathways of DNA repair. Mutations in RECQL4 are associated with three diseases Rothmund Thomson, RAPADILINO and Baller-Gerold syndrome. Using site-directed mutagenesis and recombinant proteins, we are characterizing the biochemical properties of RECQL4 patient-associated mutations. Consistently we are finding that patient mutations associated with RAPADILINO syndrome show loss of helicase but not strand exchange activity. Whereas mutations associated with RTS render the protein unstable. 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, potential protein:protein interaction partners especially following DSBs and post-translational modifications of RECQL4. 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. 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 participation to oxidative damage and more recently we evaluated 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 and specifically, RECQL5 appears to have complementary roles with WRN. Additionally, we discovered that, like WRN and BLM, RECQL5 is recruited to psoralen-induced DNA damage and that it likely plays a role in 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 thus we are continuing to screen for more optimized inhibitors.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000726-21
Application #
8736599
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
21
Fiscal Year
2013
Total Cost
$1,297,395
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code
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
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
Lu, Huiming; Shamanna, Raghavendra A; Keijzers, Guido et al. (2016) RECQL4 Promotes DNA End Resection in Repair of DNA Double-Strand Breaks. Cell Rep 16:161-73
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
Keijzers, Guido; Bohr, Vilhelm A; Rasmussen, Lene Juel (2015) Human exonuclease 1 (EXO1) activity characterization and its function on flap structures. Biosci Rep 35:
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
Fang, Evandro Fei; Scheibye-Knudsen, Morten; Jahn, Heiko J et al. (2015) A research agenda for aging in China in the 21st century. Ageing Res Rev 24:197-205

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