Diamond Blackfan Anemia (DBA) is caused by a deficiency of some ribosomal proteins to properly
process pre-ribosomal ribonucleic acid (RNA), which is ultimately
important for the translation of the genome into functional proteins. The condition is characterized by
a failure of the bone marrow to produce red blood cells, congenital
abnormalities, and a predisposition to cancer.
options, including steroid treatments and chronic transfusions, can lead
to significant morbidity. Therefore, investigation into molecular
mechanisms that drive DBA is critical to saving the lives of patients
suffering from this disease.
‘A deficiency in RPS19, the most commonly mutated ribosomal protein in Diamond Blackfan Anemia (DBA) patients, leads to the upregulation and activation of the p53 pathway.’
While it is known that p53, an important DNA repair protein, mediates
many facets of DBA, its mechanism has not, until now, been well
understood. With support from a Bone Marrow Failure Research Program
FY12 Idea Award, Dr. Kathleen Sakamoto and her team at Stanford
University has identified that a deficiency in RPS19, the most commonly
mutated ribosomal protein in DBA patients, leads to the upregulation and
activation of the p53 pathway. Furthermore, they have identified that a
target of p53, microRNA34A, is responsible for decreased red blood cell
In a recently published article in Disease Models & Mechanisms
Dr. Sakamoto's team used a zebrafish model of DBA with RPS19 and RPL11
insufficiency to further characterize the link between defects in
ribosome biogenesis, nucleotide metabolism, and the p53 pathway in DBA.
The RPS19-deficient zebrafish showed a decrease in proliferation,
enhanced activation of the ATR/ATM-CHK1/CHK2/p53 DNA damage pathway, an
imbalanced pool of nucleotides, ATP depletion, and AMPK activation.
These findings are all hallmarks of cellular energy crisis, DNA
replication stress, and thus enhanced DNA repair. When treating
zebrafish with exogenous nucleosides, a decrease in the activation of
p53 and AMPK was observed.
As blood cells are highly dependent on
salvage pathways for the production of nucleotides and are therefore
vulnerable to a stressed metabolism, red blood cells in DBA patients may
benefit from exogenous nucleosides. Nucleoside supplements are known to
be very safe and are even included in many infant formulas. This form
of supplementation may be beneficial, not only in patients with DBA, but
also for other conditions that involve the activation of the DNA damage
response, such as radiation exposure.
Furthermore, treatment of the
RP-deficient zebrafish with inhibitors of various cell cycle checkpoint
kinases decreased p53 upregulation and apoptosis while resulting in an
improvement of hematopoiesis. Therefore drugs that work to decrease DNA
damage or help increase DNA repair could be effective for the treatment
The results from this research have shed light on a previously
undiscovered link between the well-studied p53 pathway and the lesser
known pathways associated with ribosome biogenesis and nucleotide
metabolism in DBA. Uncovering this link may provide several avenues for
new treatment options for patients suffering from DBA and its current