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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Investigator-Initiated Intramural Research Projects (ZIA)
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National Institute on Aging
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Popuri, Venkateswarlu; Hsu, Joseph; Khadka, Prabhat et al. (2014) Human RECQL1 participates in telomere maintenance. Nucleic Acids Res 42:5671-88
Shamanna, Raghavendra A; Singh, Dharmendra Kumar; Lu, Huiming et al. (2014) RECQ helicase RECQL4 participates in non-homologous end joining and interacts with the Ku complex. Carcinogenesis 35:2415-24
Bendtsen, Kristian Moss; Jensen, Martin Borch; May, Alfred et al. (2014) Dynamics of the DNA repair proteins WRN and BLM in the nucleoplasm and nucleoli. Eur Biophys J :
Debrabant, Birgit; Soerensen, Mette; Flachsbart, Friederike et al. (2014) Human longevity and variation in DNA damage response and repair: study of the contribution of sub-processes using competitive gene-set analysis. Eur J Hum Genet 22:1131-6
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
Lu, H; Fang, E F; Sykora, P et al. (2014) Senescence induced by RECQL4 dysfunction contributes to Rothmund-Thomson syndrome features in mice. Cell Death Dis 5:e1226
Popp, Oliver; Veith, Sebastian; Fahrer, Jörg et al. (2013) Site-specific noncovalent interaction of the biopolymer poly(ADP-ribose) with the Werner syndrome protein regulates protein functions. ACS Chem Biol 8:179-88
Popuri, Venkateswarlu; Tadokoro, Takashi; Croteau, Deborah L et al. (2013) Human RECQL5: guarding the crossroads of DNA replication and transcription and providing backup capability. Crit Rev Biochem Mol Biol 48:289-99
Popuri, Venkateswarlu; Huang, Jing; Ramamoorthy, Mahesh et al. (2013) RECQL5 plays co-operative and complementary roles with WRN syndrome helicase. Nucleic Acids Res 41:881-99
Ramamoorthy, Mahesh; May, Alfred; Tadokoro, Takashi et al. (2013) The RecQ helicase RECQL5 participates in psoralen-induced interstrand cross-link repair. Carcinogenesis 34:2218-30

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