Cells continuously experience genome damage that, if not properly attended to, can cause developmental defects, premature aging, and increased cancer predisposition. DNA damage checkpoints defend against these consequences of genomic instability by regulating cell cycle transitions, apoptosis, and DNA repair. In mammals, the checkpoint protein Hus1 is a critical component of a pathway that responds to replication stress and a variety of DNA lesions. The Hus1- dependent pathway is essential for embryonic development, and consequently many of its biological functions in animals are not well-defined. The long-term goals of the research described in this proposal are to understand how the Hus1-dependent checkpoint pathway protects genomic integrity and to determine how defects in this mechanism affect tumorigenesis and physiological DNA damage responses. The proposed studies will advance these important objectives using a unique collection of targeted modifications at the mouse Hus1 genomic locus.
Aim one addresses how partial or complete Hus1 inactivation affects tumor development induced by activated oncogenes in order to resolve the opposing roles of Hus1 as a candidate tumor suppressor and a factor required for cancer cell survival and proliferation.
In Aim Two, the requirements for Hus1 during in vivo DNA damage responses will be determined by measuring the tissue-specific genotoxic stress responses of mice with reduced Hus1 expression, in part to gain new insights into how checkpoint function impacts sensitivity to DNA damaging anti-cancer therapies. These analyses of the physiological consequences of checkpoint dysfunction in the first two aims will be complemented by the investigation of Hus1 molecular mechanisms in Aim Three, in an effort to define the Hus1 functions that are essential for the survival of genotoxic stress and to establish how Hus1 sequence variations affect genome maintenance. Together, the proposed studies will define how an essential checkpoint mechanism functions during tumorigenesis and tissue-specific DNA damage responses, and will provide insights into the biomedical implications of checkpoint dysfunction stemming from spontaneous mutations, natural polymorphisms, or pharmacological inhibition.

Public Health Relevance

By defending against damage to the genome, DNA damage checkpoints are critical for normal embryonic development, protective responses to environmental stresses and DNA damaging chemotherapeutics, and the tumor-free survival of adult organisms. The experiments of this proposal make use of novel genetically-engineered mouse strains to analyze the biological functions of the essential DNA damage checkpoint gene Hus1. These studies hold great promise for improving the understanding of how cancers develop and how normal and neoplastic cells respond to anti-cancer therapies, as well as how these processes are influenced by Hus1 sequence variations, including spontaneous mutations and natural polymorphisms.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Etiology Study Section (CE)
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Pelroy, Richard
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Cornell University
Other Basic Sciences
Schools of Veterinary Medicine
United States
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Liu, Yi; Cussiol, José Renato; Dibitetto, Diego et al. (2017) TOPBP1Dpb11 plays a conserved role in homologous recombination DNA repair through the coordinated recruitment of 53BP1Rad9. J Cell Biol 216:623-639
Subbaramaiah, Kotha; Brown, Kristy A; Zahid, Heba et al. (2016) Hsp90 and PKM2 Drive the Expression of Aromatase in Li-Fraumeni Syndrome Breast Adipose Stromal Cells. J Biol Chem 291:16011-23
Lim, Pei Xin; Patel, Darshil R; Poisson, Kelsey E et al. (2015) Genome Protection by the 9-1-1 Complex Subunit HUS1 Requires Clamp Formation, DNA Contacts, and ATR Signaling-independent Effector Functions. J Biol Chem 290:14826-40
Okayama, Sachiyo; Kopelovich, Levy; Balmus, Gabriel et al. (2014) p53 protein regulates Hsp90 ATPase activity and thereby Wnt signaling by modulating Aha1 expression. J Biol Chem 289:6513-25
Lyndaker, Amy M; Vasileva, Ana; Wolgemuth, Debra J et al. (2013) Clamping down on mammalian meiosis. Cell Cycle 12:3135-45
Ouzounov, Dimitre G; Rivera, David R; Williams, Wendy O et al. (2013) Dual modality endomicroscope with optical zoom capability. Biomed Opt Express 4:1494-503
Lyndaker, Amy M; Lim, Pei Xin; Mleczko, Joanna M et al. (2013) Conditional inactivation of the DNA damage response gene Hus1 in mouse testis reveals separable roles for components of the RAD9-RAD1-HUS1 complex in meiotic chromosome maintenance. PLoS Genet 9:e1003320
Li, Minxing; Jirapatnakul, Artit; Biancardi, Alberto et al. (2013) Growth pattern analysis of murine lung neoplasms by advanced semi-automated quantification of micro-CT images. PLoS One 8:e83806
Daugherity, Erin K; Balmus, Gabriel; Al Saei, Ahmed et al. (2012) The DNA damage checkpoint protein ATM promotes hepatocellular apoptosis and fibrosis in a mouse model of non-alcoholic fatty liver disease. Cell Cycle 11:1918-28
Pavlova, Ina; Hume, Kelly R; Yazinski, Stephanie A et al. (2012) Multiphoton microscopy and microspectroscopy for diagnostics of inflammatory and neoplastic lung. J Biomed Opt 17:036014

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