Fanconi anemia (FA) is a genetic disease characterized by congenital defects, bone marrow failure, and cancer susceptibility. Like Bloom syndrome, the cells derived from FA patients exhibit genome instability. The unique feature of FA cells is their high sensitivity to DNA crosslinking drugs, such as mitomycin C (MMC). Eight complementation groups have been described for this disease and their corresponding genes have been identified. Five FA proteins (A, C, E, F, and G) have been suggested to interact with each other to form a multiprotein complex, the """"""""core complex"""""""", in nucleus. Recent evidence suggests that FA proteins function in a DNA damage response pathway involving breast cancer susceptibility genes 1 and 2 (BRCA1 and BRCA2, respectively). For example, following DNA damage induced by MMC, an FA protein, FANCD2, becomes mono-ubiquitinated and redistributes into nuclear foci where it colocalizes with BRCA1. In addition, one FA gene, FANCD1, has been identified as BRCA2. However, because most of FA proteins lack recognizable structure motifs and none of them has been associated with any biochemical activity, the mechanism of this disease remains unclear. We took an unbiased approach and purified a nuclear complex and demonstrated that they contain all five known core FA proteins. Importantly, this complex contains many other components, including DNA modifying proteins and protein modifying enzymes. We already demonstrated that this complex has multiple activity in vitro. Some of the new components we identified are also missing in FA cells. We believe that studies of these new components will provide key clues for our understanding the mechanism of this disease. A paper describing some of these components have been submitted for publication.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Intramural Research (Z01)
Project #
1Z01AG000688-01
Application #
6668131
Study Section
(LG)
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2002
Total Cost
Indirect Cost
Name
Aging
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Scherling, Carole S; Zakrzewski, Jessica; Datta, Samir et al. (2017) Mistakes, Too Few to Mention? Impaired Self-conscious Emotional Processing of Errors in the Behavioral Variant of Frontotemporal Dementia. Front Behav Neurosci 11:189
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Wang, Weidong (2007) Emergence of a DNA-damage response network consisting of Fanconi anaemia and BRCA proteins. Nat Rev Genet 8:735-48
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