Somatic genetic rescue of a germline ribosome
assembly defect
By
Aparna R. Biswas
Outline
• Background
• Introduction
• Result
• Summery
• Future direction
Eukaryotic initiation factor 6 (eIF6)
• eIF6 is important for 60S
biogenesis in the nucleolus
• Release of eIF6 from 60S in the
cytoplasm allows formation of
80S complex
• If not released, 60S is unable to
join 40S
o Leads to reduction in active
80S levels
o Decrease in translational
efficiency
o Observed in SDS disease
Miluzio, A., A. Beugnet, V. Volta and S. Biffo (2009). "Eukaryotic initiation factor 6 mediates a
continuum between 60S ribosome biogenesis and translation." EMBO reports 10(5): 459-465.
One of the models for eIF6 release from 60S: SBDS-mediated
• SBDS and Elongation Factor-like
GTPase 1 (EFL1) – release eIF6
from 60S
• SBDS mutations leads to defects in
eIF6 release and 60S maturation
eIF6
Ref: Weis, F., E. Giudice, M. Churcher, L. Jin, C. Hilcenko, C. C. Wong, D. Traynor, R. R. Kay and A. J. Warren (2015). "Mechanism
of eIF6 release from the nascent 60S ribosomal subunit." Nature structural & molecular biology 22(11): 914-919.
Shwachman-Diamond syndrome or SDS
• Rare genetic (recessive)
disorder/ribosomopathy
• eIF6 release from 60S is inhibited
• Symptoms
o Hematological, skeletal, pancreatic
and neuronal abnormalities, nutrient
malabsorption.
o Possesses a high risk of developing
acute myeloid leukemia.
Ref: Archives of Disease in Childhood, 1980, 55, 331-347,
Shwachman's syndrome- A review of 21 cases
90% of the patients with this disorder carry mutation in SBDS (Shwachman-Bodian-Diamond syndrome protein)
SBDS and eIF6 in SDS patients
o Also seen in patients with
inactivating SBDS mutations
Ref: Roberto Valli, Annalisa Frattini & Antonella Minelli (2017) Shwachman-Diamond syndrome:
diagnosis, pathogenesis and prognosis, Expert Opinion on Orphan Drugs, 5:10, 753-767
Introduction
• Somatic mutation
• Acquired after birth, accumulate with age
• Causes age related disease, tumorigenesis
• Can be beneficial- somatic genetic rescue
• Found in eIF6 gene in SDS patients
• Indirect SGR?
• Beneficial for cell?
Results
Figure:1 Multiple somatic genetic events target the EIF6 gene in hematopoietic cells in
SDS.
Figure:1 Contd.
Figure:2 Somatic EIF6 mutations identified in SDS.
Figure:2 Contd.
Figure:3 Spectrum of somatic EIF6 mutations in SDS hematopoietic cells.
Figure:3 Contd.
Figure:3 Contd.
Figure:4 SDS-related eIF6 mutations map to three regions.
Figure.5 Functional consequences of SDS-related eIF6 mutations.
Figure:5 Contd.
Figure:6 N106S mutation disrupts the H-bonding capacity of the eIF6-uL14
interaction interface.
Figure:6 Contd.
Figure:7 eIF6 missense mutations fully rescue the larval lethality of Sbds-deficient
D. melanogaster.
Figure:7 Contd.
Figure:7 Contd.
Summery
Figure:8 Schematic representation of EIF6 somatic genetic rescue (SGR)
mechanisms in SDS.
Future direction
• Is SGR evident in other cells other than hematopoietic stem cells?
• Is eIF6 mutation beneficial for patients? What are the effects of
mutant clones to disease outcome?
• Are eIF6 somatic mutations related to TP53 somatic mutation?
Questions!!!