Fanconi Anemia

1
Fanconi Anemia FANCD2
http//locus.umdnj.edu/nigms/pathways/fanc_diagram
.html
2
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/fanconianemi
a/
3
Developmental Results of FA
Shorter digits and slightly unattached thumbs of
toddler
Small stature of 3- year old with FA
http//www.emedicine.com/rc/rc/pimages/i30/anemia.
htm
4
Diagnosis and Treatment

• The most common test to diagnose FA is the
  Chromosome Breakage Test
• There are no real treatments for FA

5
http//www.bloodjournal.org/cgi/content/full/101/3
/822
6
Expressivity of FA (and penetrance of certain
phenotypes)

• Severity of clinical phenotype is a result of

7
FA is a multigenic disease

• 9 genes
• We will discuss one of the FA proteins, FANCD2

8
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

9
The Cell Biology of FANCD2
Thompson, et al. Environmental and Molecular
Mutagenesis 45128-142. (2005).
10
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.

11
Details of FANCD2 and how it stabilizes
replication forks

• What does it do?
• With what does it work?

12
FANCD2 pathway
http//www.nature.com/nm/journal/v8/n6/images/nm06
02-555-F1.gif
13
Without proper functioning

• In the cell cycle stages
• During replication
• The results include, but arent limited to,
  non-homologous end joining (NHEJ) in the
  following ways

14
Possibilities in FA cells
Thompson, et al. Environmental and Molecular
Mutagenesis 45128-142. (2005).
15
FANCD2 Mouse knockouts

• Are mice good models?
• How are mutants made?
• What was the result?
• What does this tell us?
• What about other mutants?

16
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

17
Mouse knockouts continued

• Mouse mutant phenotype similar to humans
• Was anything different?

18
Wild-type
mutant
http//www.genesdev.org/cgi/content/full/17/16/202
1
19
http//www.genesdev.org/cgi/content/full/17/16/202
1
20
FANCD2 and other cancer genes

• FA and BRCA2
• FA and BRCA1
• FANCD2 and common cancers

21
Take-home message

• FA or a mutation in FANCD2 hasnt been shown to
  directly cause cancer

22
Text References

• Published online before print July 31, 2003,
  10.1101/gad.1103403GENES DEVELOPMENT
  172021-2035, 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