FANCD2 and Fanconi’s Anemia

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FANCD2 and Fanconi’s Anemia Brianna Eskola

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 http://www.radswiki.net

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

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

DNA crosslink www.bioscience.org/2004/v9/af/1246/fig1.jpg

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

DNA repair

FANCD2 Pathways www.nature.com

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

Rad51 and Brca2 normal in FANCD2 Mutants

The Big Picture

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 https://www.blueshieldca.com

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

References http://www.nlm.nih.gov/medlineplus/ency/article/000334.htm - medicine plus http://www.fanconi.org/aboutfa/FA.htm - Fanconi Research Fund theyorf.blogspot.com/2007/10/fanconi-anaemia-... http://www.nature.com/nm/journal/v8/n6/full/nm0602-555.html - 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. 2003