Fanconi anemia (FA) is a rare genetic disease characterized by pediatric bone marrow failure and congenital abnormalities. The FA genes are also frequently mutated in cases of acquired bone marrow failure. The FA proteins function cooperatively with the tumor suppressor proteins BRCA1 and BRCA2 (FANCD1) in the FA- BRCA pathway to repair damaged DNA and to prevent cellular transformation. A critical step in the activation of the FA-BRCA pathway is the mono-ubiquitinaton of the FANCD2 and FANCI proteins. Importantly, the cellular regulation of FANCD2 and FANCI mono-ubiquitination remains poorly understood. Furthermore, the physiological function of mono-ubiquitinated FANCD2 and FANCI in the DNA damage response remains largely unknown. The major goal of this research proposal is to systematically address these critical unanswered questions. Towards this goal, we have recently determined that the p21 cyclin dependent kinase inhibitor plays an important role in the regulation of DNA damage-inducible FANCD2 mono-ubiquitination. Furthermore, using in silico bioinformatic approaches, we have identified a putative ubiquitin-binding domain (UBD) and a proximal ubiquitin-like domain (UbL) in FANCD2. Preliminary experiments have confirmed a non- covalent interaction between FANCD2 and ubiquitin. In this proposal, we plan to systematically characterize the role of p21, as well as the putative UBD and UbL domains, in the mono-ubiquitination of FANCD2 and the activation of the FA-BRCA pathway. As defective FANCD2 and FANCI mono-ubiquitination is a cellular feature of >90% of FA patients as well as a subset of cases of marrow aplasia in the general (non-FA) population, the study of the regulation and function of this post-translational modification stands to impart a greater understanding of bone marrow maintenance and stability in general.

Public Health Relevance

Fanconi anemia (FA) is a rare disease characterized by progressive bone marrow failure. The FA pathway is also frequently inactivated in cases of acquired bone marrow failure. A greater understanding of the regulation and function of the FA proteins will lead to improved diagnostic and therapeutic approaches to FA, and improve our understanding of bone marrow maintenance and stability in general.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL101977-04
Application #
8627198
Study Section
Molecular and Cellular Hematology (MCH)
Program Officer
Qasba, Pankaj
Project Start
2011-04-01
Project End
2015-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
4
Fiscal Year
2014
Total Cost
$676,930
Indirect Cost
$219,593
Name
University of Rhode Island
Department
Anatomy/Cell Biology
Type
Schools of Earth Sciences/Natur
DUNS #
144017188
City
Kingston
State
RI
Country
United States
Zip Code
02881
Boisvert, Rebecca A; Rego, Meghan A; Azzinaro, Paul A et al. (2013) Coordinate nuclear targeting of the FANCD2 and FANCI proteins via a FANCD2 nuclear localization signal. PLoS One 8:e81387