Fanconi Anemia & FANCD2

http://locus.umdnj.edu/nigms/pathways/fanc_diagram.html

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…

http://www.bloodjournal.org/cgi/content/full/101/3/822

Expressivity of FA (and penetrance of certain phenotypes)

Severity of clinical phenotype is a result of:

FA is a multigenic disease

9 genes

We will discuss one of the FA proteins, FANCD2

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.

Details of FANCD2 and how it stabilizes replication forks

What does it do?

With what does it work?

FANCD2 pathway

http://www.nature.com/nm/journal/v8/n6/images/nm0602-555-F1.gif

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

Mouse knockouts continued…

Mouse mutant phenotype similar to humans

Was anything different?

http://www.genesdev.org/cgi/content/full/17/16/2021

Wild-type mutant

http://www.genesdev.org/cgi/content/full/17/16/2021

FANCD2 and other cancer genes

FA and BRCA2

FA and BRCA1

FANCD2 and common cancers

Take-home message

FA or a mutation in FANCD2 hasn’t been shown to directly cause cancer…

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