Download MDM2 and Soft Tissue Sarcomas

Scientific Reports
Nbr1, a Receptor for ESCRT-Dependent Endosomal Microautophagy in
Fission Yeast
Noboru Mizushima1 et al.,
Department of Biochemistry and Molecular Biology, Graduate School and Faculty of Medicine, The University of
Tokyo,
Tokyo 113-0033, Japan
In this issue of Molecular Cell, Liu et al. (2015) report that
fission yeast Nbr1, sharing a partial homology to
the mammalian macroautophagy receptor NBR1, acts as a
receptor for ESCRT-dependent endosomal microautophagy that
delivers two hydrolytic enzymes from the cytosol to the vacuole.
Endosomal sorting complexes required for transport (ESCRT)
7
SPOP Promotes Ubiquitination and Degradation of the ERG Oncoprotein
to Suppress Prostate Cancer Progression
Wenjian Gan wt al.,
Department of Pathology, Cancer Research Institute, Beth Israel Deaconess Cancer Center, Beth Israel
Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
The ERG gene is fused to TMPRSS2 in approximately 50% of
prostate cancers (PrCa), resulting in its overexpression. However,
whether this is the sole mechanism underlying ERG elevation in
PrCa is currently unclear. Here we report that ERG ubiquitination
and degradation are governed by the Cullin 3-based ubiquitin ligase
SPOP and that deficiency in this pathway leads to aberrant
elevation of the ERG oncoprotein. Specifically, we find that
truncated ERG (ΔERG), encoded by the ERG fusion gene, is
stabilized by evading SPOP-mediated destruction, whereas prostate
cancer-associated SPOP mutants are also deficient in promoting
ERG ubiquitination. Furthermore, we show that the SPOP/ERG
interaction is modulated by CKI-mediated phosphorylation.
Importantly, we demonstrate that DNA damage drugs,
topoisomerase inhibitors, can trigger CKI activation to restore the
SPOP/ΔERG interaction and its consequent degradation.
Therefore, SPOP functions as a tumor suppressor to negatively
regulate the stability of the ERG oncoprotein in prostate cancer.
8
P16INK4a Upregulation Mediated by SIX6 Defines Retinal Ganglion Cell
Pathogenesis in Glaucoma
Dorota Skowronska-Krawczyk et al.,
Institute of Molecular Medicine, Peking University, Beijing 100871, China
Glaucoma, a blinding neurodegenerative disease, whose risk
factors include elevated intraocular pressure (IOP), age, and
genetics, is characterized by accelerated and progressive retinal
ganglion cell (RGC) death. Despite decades of research, the
mechanism of RGC death in glaucoma is still unknown. Here, we
demonstrate that the genetic effect of the SIX6 risk variant
(rs33912345, His141Asn) is enhanced by another major POAG risk
gene, p16INK4a (cyclin-dependent kinase inhibitor 2A, isoform
INK4a). We further show that the upregulation of homozygous SIX6
risk alleles (CC) leads to an increase in p16INK4a expression, with
subsequent cellular senescence, as evidenced in a mouse model of
elevated IOP and in human POAG eyes. Our data indicate that
SIX6 and/or IOP promotes POAG by directly increasing p16INK4a
expression, leading to RGC senescence in adult human retinas. Our
study provides important insights linking genetic susceptibility to the
underlying mechanism of RGC death and provides a unified theory
of glaucoma pathogenesis.
9
USP7 Acts as a Molecular Rheostat to Promote WASH-Dependent
Endosomal Protein Recycling and Is Mutated in a Human
Neurodevelopmental
Disorder
Yi-Heng
Hao et al.,
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Endosomal protein recycling is a fundamental cellular process
important for cellular homeostasis, signaling, and fate determination
that is implicated in several diseases. WASH is an actin-nucleating
protein essential for this process, and its activity is controlled
through K63-linked ubiquitination by the MAGE-L2-TRIM27 ubiquitin
ligase. Here, we show that the USP7 deubiquitinating enzyme is an
integral component of the MAGE-L2-TRIM27 ligase and is essential
for WASH-mediated endosomal actin assembly and protein
recycling. Mechanistically, USP7 acts as a molecular rheostat to
precisely fine-tune endosomal F-actin levels by counteracting
TRIM27
auto-ubiquitination/degradation
and
preventing
overactivation of WASH through directly deubiquitinating it.
Importantly, we identify de novo heterozygous loss-of-function
mutations of USP7 in individuals with a neurodevelopmental
disorder, featuring intellectual disability and autism spectrum
disorder. These results provide unanticipated insights into
endosomal trafficking, illuminate the cooperativity between an
ubiquitin ligase and a deubiquitinating enzyme, and establish a role
WASH
is nucleation-promoting
factor (NPF) at thedisease.
surface of endosomes.
for
USP7
in human neurodevelopmental
10
Distinct but Concerted Roles of ATR, DNA-PK, and Chk1 in Countering
Replication Stress during S Phase
Rémi Buisson et al.,
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02129, USA
The ATR-Chk1 pathway is critical for DNA damage responses
and cell-cycle progression. Chk1 inhibition is more deleterious
to cycling cells than ATR inhibition, raising questions about ATR
and Chk1 functions in the absence of extrinsic replication
stress. Here we show that a key role of ATR in S phase is to
coordinate RRM2 accumulation and origin firing. ATR inhibitor
(ATRi) induces massive ssDNA accumulation and replication
catastrophe in a fraction of early S-phase cells. In other Sphase cells, however, ATRi induces moderate ssDNA and
triggers a DNA-PK and Chk1-mediated backup pathway to
suppress origin firing. The backup pathway creates a threshold
such that ATRi selectively kills cells under high replication
stress, whereas Chk1 inhibitor induces cell death at a lower
threshold. The levels of ATRi-induced ssDNA correlate with
ATRi sensitivity in a panel of cell lines, suggesting that ATRiinduced ssDNA could be predictive of ATRi sensitivity in cancer
cells.
RRM2 (Ribonucleotide Reductase M2)
ATR (Ataxia Telangiectasia)
11