The long-term objectives of this project are to understand the mechanisms and functions of DNA damage checkpoints in embryonic development and the chemotherapy response. Cells execute a protective response to chemotherapies which cause DNA damage or inhibit DNA replication. This involves a complex signaling network driven by the ATR (Ataxia-Telangiectasia and Rad3-related) kinase and its upstream regulator TopBP1 (DNA Topoisomerase ll-Binding Protein 1). Besides serving this protective function, ATR and TopBP1 also maintain genomic integrity during unperturbed DNA replication and embryonic development, and inherited mutations that disrupt the ATR signaling pathway cause human developmental disorders. Thus, pharmacologic inhibition of DNA damage checkpoints to sensitize cancer cells to chemotherapy is likely to cause side effects. TopBP1 has eight BRCT (BRCA1 C-terminal) protein interaction domains and is multifunctional, also acting in DNA replication, DNA repair, and transcription. TopBP1 likely participates in such diverse aspects of DNA metabolism by acting as a central component of multiple functionally distinct subcomplexes, but these various subcomplexes remain to be defined. The current proposal consists of three aims.
The first Aim i s focused on characterizing an interaction between TopBP1 and an entirely novel protein called TICRR (TopBP1-interacting checkpoint and replication regulator). TICRR interacts with the first two BRCT domains of TopBP1 and is required for DNA replication initiation and cell cycle arrest following DNA damage.
The second Aim i s focused on identifying and characterizing novel TopBP1 and TICRR protein interactions.
The third Aim determines the functions of TICRR and TopBP1 during zebrafish embryonic development. Knowledge from these studies will lead to a better understanding of DNA damage responses to chemotherapy as well as illuminate the molecular underpinnings of human developmental disorders caused by defects in ATR signaling. Understanding differences between how checkpoint proteins function in normal cell proliferation versus in the chemotherapy response will facilitate the development of treatment strategies that inhibit checkpoint signaling in tumors, while leaving normal cells unperturbed.

Public Health Relevance

Commonly used cancer treatments block DNA replication and damage DNA, thereby killing both cancer cells and healthy proliferating cells alike. Broadly, we aim to reveal how cells replicate DNA and respond to DNA damage so that we may develop cancer treatments with fewer side effects. Specifically, we will elucidate how a protein called TopBP1 acts with other proteins in DNA replication and the DNA damage response.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
4P20GM103636-04
Application #
9015458
Study Section
Special Emphasis Panel (ZGM1)
Project Start
Project End
Budget Start
2016-03-01
Budget End
2017-02-28
Support Year
4
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Oklahoma Medical Research Foundation
Department
Type
DUNS #
077333797
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104
Bhaskaran, Shylesh; Pharaoh, Gavin; Ranjit, Rojina et al. (2018) Loss of mitochondrial protease ClpP protects mice from diet-induced obesity and insulin resistance. EMBO Rep 19:
Siefert, Joseph C; Clowdus, Emily A; Goins, Duane et al. (2018) Profiling DNA Replication Timing Using Zebrafish as an In Vivo Model System. J Vis Exp :
Borga, Chiara; Park, Gilseung; Foster, Clay et al. (2018) Simultaneous B and T cell acute lymphoblastic leukemias in zebrafish driven by transgenic MYC: implications for oncogenesis and lymphopoiesis. Leukemia :
Wren, Jonathan D (2018) Algorithmically outsourcing the detection of statistical errors and other problems. EMBO J 37:
Georgescu, Constantin; Wren, Jonathan D (2018) Algorithmic identification of discrepancies between published ratios and their reported confidence intervals and P-values. Bioinformatics 34:1758-1766
Snider, Timothy A; Richardson, Arlan; Stoner, Julie A et al. (2018) The Geropathology Grading Platform demonstrates that mice null for Cu/Zn-superoxide dismutase show accelerated biological aging. Geroscience 40:97-103
Sansam, Courtney G; Pietrzak, Katarzyna; Majchrzycka, Blanka et al. (2018) A mechanism for epigenetic control of DNA replication. Genes Dev 32:224-229
de Castro, Rodrigo O; Previato, Luciana; Goitea, Victor et al. (2017) The chromatin-remodeling subunit Baf200 promotes homology-directed DNA repair and regulates distinct chromatin-remodeling complexes. J Biol Chem 292:8459-8471
Wang, Hong-Cheng; Qian, Liangyue; Zhao, Ying et al. (2017) Downregulation of E Protein Activity Augments an ILC2 Differentiation Program in the Thymus. J Immunol 198:3149-3156
Sun, Chengyi; Berry, William L; Olson, Lorin E (2017) PDGFR? controls the balance of stromal and adipogenic cells during adipose tissue organogenesis. Development 144:83-94

Showing the most recent 10 out of 57 publications