Download Fancd2 Fanconi anemia protein complementation group d2

FANCD2
FANCONI ANEMIA PROTEIN
COMPLEMENTATION GROUP D2
by Meredith Binkley
Fanconi Anemia as a disease
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Rare- 10-20 new cases in
the US each year
Symptoms include
hematological
abnormalities (anemia),
radial and thumb
hyperplasia, café au lait
spots, short stature,
infertility
Other less severe
symptoms include
unexplained fatigue, nose
bleeds, and easy bruising
Fanconi Anemia creates a predisposition to cancer
Leukemia and squamous cell carcinoma are commonly associated with Fanconi Anemia
People with Fanconi Anemia fail to develop leukocytes, red blood cells and platelets
Inherited in an autosomal recessive disorder
Bone marrow transplantation is a treatment but this increases the chance of cancer
The cellular phenotype
FA cells have a hypersensitivity to DNA
damaging chemicals. This results in apoptosis.
FANCD2 is part of a family of FANC proteins
A mutation in different FANC proteins can result
in Fanconi Anemia
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History of FANCD2 and FA
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Discovered by Guido Fanconi
in 1927
In 1992 Strathdee et al.
conducted a study suggesting
that there was more than one
gene that caused the disease.
He discovered 4
complementation groups
2001 Timmers et al was the
first to clone FANCD2 via
positional cloning. They also
discovered the heterogeneous
nature of FANCD.
2001, Alan D'Andrea linked
FANCD2 to BRCA1
“Fluorescence microscopy shows that
D, usually diffusely located throughout
the nucleus (top left), concentrates into
nuclear foci after DNA damage (top
right).”
Focus, Harvard’s Medical Journal
The two pathways with FANCD2
In response to
Ionizing
radiation,
FANCD2 is
phosphorylate
d
In response to
Mitomycin C a
monoubiquitin
ation event
occurs
A closer look at both pathways
ATM pathway
occurs due to
a double
stranded
break
BRCA1
pathway
occurs when
homologous
recombination
can fix the
situation.
The FANCD2/ BRCA pathway
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A nuclear core
complex
monoubiquitinates
FANCD2
Monoubiquitinatio
n in response to
DNA damage
activates the
protein
FANCD2 then
takes actions to
help with HR
http://www.hematology.org
A closer look at the NCC
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FANCA, FANCB,
FANCC, FANCE,
FANCF, FANCG,
FANCL AND FANCM
all group together
FANCL is the actual
protein that
monoubiquitinates
FANCD2
The FANCD2/ ATM Pathway
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Activated in
response to a
double stranded
break
Believed to be
connected to Sphase check
point, but exact
link is unknown
FA cells spend 310 times longer
ins late s-phase
arrest after cross
linking
“Perhaps FANCD2, with signaling input
from the FA proteins and ATM, may
determine the choice between these
alternative pathways.”
-Markus Grompe, Department of Molecular and Medical Genetics Oregon Health Science University Portland
Now that we know the function, how
does it cause cancer?
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Tumor formation is not
completely understood with
FANC family of proteins
It takes more than one
mutation to lead to cancer
FANC mutations elevate
apoptosis
It is hypothesized that a
mutation of a resistance to
apoptosis will be selected for
at a cellular level
A mutation in p53 that causes
cells to avoid apoptosis will
be selected for
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There are high alterations of
p53 in sporadic tumors in FA
patients
More evidence in mouse
mutants that also had a
heterozygous p53 gene
Double mouse mutants
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Took FANCD2 knock
out mice
Crossed them with p53
null mutant mice
Came up with a
FANCD2-/-/p53 +/double mutant mouse
These mice developed
tumors much earlier
than FANCD2-/- mice
Scott Houghtaline and colleges at the Oregon Health and Science University
More on Mice Mutants
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In 2000, Cheng et al
created FANCA knockout
mice
Viable with no
development
abnormalities
Had a slightly decreased
platelet count,
hypogonadism and
impaired fertility
Also had chromosomal
instability and were
sensitive to Mitomycin C
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However, FANCD2 mouse
mutants are smaller,
develop epithelial tumors
and are germ-cell
deficient
Oddly, there are no
defects in the ATM
mediated s-phase
checkpoint
Treatments
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A treatment for the FA
disease is a bone
marrow transplant
However finding a
match can be hard.
Hormones can stimulate
blood cell production
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Enbrel drug therapyblock tumor necrosis
factor (TNF)
Used in arthritis and
people with immune
disease
Has lots of negative side
effects for FA patients:
lower ability to fight
infections, increases
chance of leukemia
Cincinnati Children’s Hospital
Henry’s story…putting
a face to the disease
Henry was a boy who suffered from Fanconi Anemia. His
parents wanted him to have a bone marrow transplant but could
not find a donor. They decided to have another baby. Naturally
the baby would have an 18% chance of matching Henry and
not having Fanconi anemia. Mark Hughes, from the National
Institute of Health was going to test the embryo at the eight cell
stage before it was implanted. This would give the couple a
second child without FA and would save their first child’s life.
Hughes’ work was stopped after it was revealed in 1997 that
he was violating a federal ban on human embryo research.
Henry never received his sibling and died on December 11,
2002.
His parents later formed A Hope for Henry an organization that
donated toys to children in hospitals.
“Vetoing Henry,” The Washington Post
Work Cited
Eike Gallmeier and Scott E. Kern , “Targeting Fanconi Anemia/BRCA2 Pathway
Defects in Cancer: The Significance of Preclinical Pharmacogenomic Models,”
Clinical Cancer Research 13, 4-10, January 1, 2007
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Alan D.D’Andrea* and Markus Grompe‡, “THE FANCONI ANAEMIA/BRCA
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PATHWAY,” Nature. VOLUME 3, JANUARY 2003.
Markus Grompe, “FANCD2: A branch-point in DNA damage response?”
Medicine 8, 555 - 556 (2002) .
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Scott Houghtaling, “Epithelial cancer in Fanconi anemia complementation group
D2 knockout mice,” Genes & Dev. published online Jul 31, 2003.
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Gurtan, A. D’Andrea, A. “Dedicated to the core: Understanding the Fanconi anemia
complex” Elsevier. 2006. pg 1119-1125
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Thompson, L. Hinz, J. Yamada, N. Jones, N. “How Fanconi anemia proteins promor
the four Rs: Replication, Recombination, Repair and Recovery.” Environmental and
Molecular Mutagenesis. 2005 pgs. 128-142.
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Houghtaling, S. et al. “Heterozygosity for p53 Accelerates epithelial Tumor
Formation in Fanconi Anemia complementation group D2 knockout Mice.” Molecular
Biology, Pathobiology and Genetics. January 1, 2005.
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