Fanconi Anemia & FANCD2 http://locus.umdnj.edu/nigms/pathways/fanc_diagram.html
Dec 19, 2015
What is FA?
Rare autosomal recessive disorder
Characterized by… Progressive bone
marrow failure Cancer
susceptibility… Congenital
malformations…
Increased apoptosis in hemopoietic cells
Prolonged G2 phase
http://www.fanconicanada.org/sys-tmpl/fanconianemia/
Developmental Results of FA
http://www.emedicine.com/rc/rc/pimages/i30/anemia.htm
Shorter digits and slightly unattached thumbs of toddler Small stature of 3-
year old with FA
Diagnosis and Treatment
The most common test to diagnose FA is the Chromosome Breakage Test
There are no real treatments for FA…
Expressivity of FA (and penetrance of certain phenotypes)
Severity of clinical phenotype is a result of:
Overview
Other FA proteins in nucleus and cytoplasm
The nuclear core complex monoubiquitinates FANCD2
Repair mechanisms can come and repair problem
DNA can replicate properly
The Cell Biology of FANCD2
Thompson, et al. Environmental and Molecular Mutagenesis 45:128-142. (2005).
Details of FANCD2 and how it stabilizes replication forks
FANCD2 protein increases during S-phase.
FANCD2 is monoubiquitinated at Lys 561 (only if the cell has the full FA complex).
Monoubiquitination of FANCD2 is mediated by other FA proteins.
Without proper functioning…
In the cell cycle stages:
During replication:
The results include, but aren’t limited to, non-homologous end joining (NHEJ) in the following ways:
Possibilities in FA cells
Thompson, et al. Environmental and Molecular Mutagenesis 45:128-142. (2005).
FANCD2 Mouse knockouts
Are mice good models?
How are mutants made?
What was the result?
What does this tell us?
What about other mutants?
Mouse knockouts continued…
Fancd2 -/- were smaller than the rest of the non-mutant litter
Smaller testes and lower sperm and egg count
This tell us that FANCD2 is involved in germ cell development and survival
Text References
Published online before print July 31, 2003, 10.1101/gad.1103403GENES & DEVELOPMENT 17:2021-2035, 2003 Scott Houghtaling, Cynthia Timmers, Meenakshi Noll, Milton J. Finegold3, Stephen N. Jones4, M. Stephen Meyn2 and Markus Grompe1
Epithelial cancer in Fanconi anemia complementation group D2 (Fancd2) knockout mice