1. FANCD2 and Fanconi’s Anemia
Brianna Eskola

2. Fanconi’s Anemia Autosomal recessive Affects 1/100,000
Bone marrow disease
Loss of blood cells
Seen before age 12
Symptoms
Abnormal heart, lungs, and
kidneys
Bone problems
Abnormal hands
Pigment changes in skin
Can lead to AML
Squamous cell carcinomas

3. Fanconi's Anemia Cells Elevated apoptosis Prolonged G2 phase
Chromosome instability with telomere shortening
Sensitivity to DNA interstrand crosslinks
bp1.blogger.com/.../s320/BreaksFanconi.gif

4. FANCD2 and the NCCFA Tumor Suppressor Highly conserved
Primary role: recruit FANCD1/BRCA2
FA proteins; FANCA/B/C/E/F/G/L = nuclear core complex, NCCFA
The NCCFA complex stabilizes replication forks
theyorf.com/fanconi-anemia

5. DNA crosslink

6. FANCD2 and FA protein pathway
theyorf.com/fanconi-anemia

7. DNA repair

8. FANCD2 Pathways

9. Knockout Mice Fancd2 -/- Viable Sensitive to Mytomycin C
Developmental delay
More severe phenotype than other FA mutants
High incidence of tumor development
Do not develop Anemia
Not due to ATM-dependent S-phase checkpoint

10. Rad51 and Brca2 normal in FANCD2 Mutants

11. The Big Picture

12. Testing Treatment Regular blood count checks Chromosome breakage test
Growth factors
Bone marrow transplant
Anti-biotics
Blood transfusions
Chromosome breakage test
Complete blood count test
Bone marrow biopsy
medical-genetics.net/Laboratory/Breakage.htm

13. Review FANCD2 serves two purposes: If FANCD2 mutated:
Stalls the replication fork to recruit BRCA1 to repair interstrand crosslinks in DNA
To arrest cell in S-phase
If FANCD2 mutated:
Hypersensitive to DNA crosslinks with high rate of apoptosis – anemia
Avoid apoptosis creates clones with cytogenic defects– cancer especially AML

14. References
- medicine plus
- Fanconi Research Fund
theyorf.blogspot.com/2007/10/fanconi-anaemia-...
- nature medicine
Thompson, Larry H. et al. How Fanconi Anemia Proteins Promote the Four Rs: Replication, Recombination, Repair, and Recovery. 2005
Houghtaling, Scott. et al. Epithelial Cancer in Fanconi Anemia Complementation Group D2 Knockout Mice