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Genetic Regulations of Degradation Pathways
in human body

GENETIC REGULATION OF DEGRADATION PATHWAYS IN HUMAN
BODY
Introduction:
 Proteins destined for lysosomal degradation can reach the lysosome by a variety of means and
autophagy is one regulated pathway of lysosomaldegradation in mammalian cells
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PROTEIN DEGRADATION PATHWAYS
 The levels of proteins within cells are determined not only by rates of synthesis, but also by rates of
degradation
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 Many rapidly degraded proteins function as regulatory molecules, such as transcription factors
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 Other proteins are rapidly degraded in response to specific signals, providing another mechanism for
the regulation of intracellular enzyme activity
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In eukaryotic cells, two
major pathways
 ubiquitin-proteasome pathway
 lysosomal proteolysis—mediate protein degradation
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Autophagosomal and
multivesicular body (MVB) pathways merge at
the lysosome and share a dependence on vATPase activity (inhibited by bafilomycin)
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Proteasomal
inhibitors include lactacystin and epoxomicin
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The
domain structures shown are for the human
representatives of each protein family, except
for yeast Ddi1, the human ortholog of which
does not contain a UBA domain
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Lysosomal Proteolysis
 The other major pathway of protein degradation in eukaryotic cells involves the uptake of proteins by
lysosomes
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They have several roles in cell metabolism, including the digestion of
extracellular proteins taken up by endocytosis as well as the gradual turnover of cytoplasmic
organelles and cytosolic proteins
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Therefore, in order to be degraded by lysosomal proteolysis,
cellular proteins must first be taken up by lysosomes
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These
vesicles then fuse with lysosomes, and the degradative lysosomal enzymes digest their contents
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 The lysosome system
Lysosomes contain various digestive
enzymes, including proteases
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g
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This fusion yields a phagolysosome, which
digests the contents of the
autophagosome
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Autophagy, endocytosis and the MVB pathway,
chaperone mediated autophagy (CMA) and
microautophagy (MA) are depicted
...
[3]

Lysosomal signaling in control of degradation pathways
Signaling pathways central for cell growth and survival adjust the flux of cargo and regulate the biogenesis of
lysosomal degradation pathways The most prominent example is mTOR signaling, which integrates signaling
from nutrients, growth factors, and energy availability
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They are found in various subcellular locations and fulfill different tasks
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[4]

Figure : Schematic presentation of lysosomal signaling complexes and their roles in lysosomal degradation
pathways
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RNA molecules with
defects in processing, folding, or assembly with proteins are identified and rapidly degraded by the
surveillance machinery
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Degradation of Different Types of RNA in Eukaryotes
Several different classes of RNA degradation can potentially be discriminated
...
Such maturation pathways are integral to the processing of
all classes of RNA and removal of the discarded material probably dominates total RNA degradation
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Similarly, most
characterized examples from the seemingly large numbers of unstable ncRNAs undergo rapid and continuous
degradation
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Quality control: Surveillance pathways appear to be active on all classes of eukaryotic RNA, constantly
identifying and degrading defective RNAs and RNA-protein complexes
...
[5]

Processing and Degradation of RNA Polymerase II Transcripts
 Processing of RNA Pol II transcripts can be divided into six phases
...
Failure of this step is predicted to lead
to degradation by 5′ exonuclease Rat1 and
transcription termination
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If clusters of Nrd1-Nab3 sites are encountered
during the Ser5P period, transcription is
terminated, followed by 3′ exonucleolytic
degradation This leads to complete
degradation or sn(o)RNA 3′-end formation
depending on the nature of transcript
...
This is debranched by Dbr1 and
degraded by exonucleases from both ends,
leading, in most cases, to complete
degradation or to maturation of intronencoded snoRNAs
...
The 3′ end of the RNA
remains on the elongating polymerase but is
no longer capped
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Export: mRNA is packaged and
exported to the cytoplasm
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Either coupled
to nuclear export or occurring soon thereafter, the transcript undergoes a primary round of translation,

followed by degradation if premature stop codons are detected
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Translation: mRNA undergoes multiple rounds of translation, during which time the poly(A) tail is
progressively shortened
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[6]

siRNA- and miRNA-Directed RNA Degradation
 RNA polymerase II also generates the precursors to the very small RNA species, miRNAs, siRNAs,
and piRNAs, which in some cases target mRNAs and other RNAs for degradation
...
The effectors of
miRNA and siRNA function are two related RNP complexes, the cytoplasmic RISC and the nuclear
RNA-induced transcriptional silencing complex
(RITS)
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This results in decreased translation and increased
5′ and 3′ degradation
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Cotranscriptional cleavage
by a complex that includes the double-strand
endonuclease Drosha generates a pre-miRNA

...
In contrast, exogenously
added and endogenously synthesized long,
perfectly complementary double-stranded RNAs
are processed to small-interfering RNAs
(siRNAs) by the dicer complex alone
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Cooper GM
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2nd edition
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5
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7
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Protein Degradation
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Clague
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2006;Volume 143, Issue 5, p682–685
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C
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Kaushik, A
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Cuervo , Autophagy, 2 (2006), pp
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Settembre, A
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Ballabio , Nat Rev Mol Cell Biol, 14 (2013), pp
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P
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E
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R
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Science, 319 (2008), pp
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Schwede, L
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Luther, M
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Stoecklin, C
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, 36
(2008), pp
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Slomovic, D
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Geiger, G
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Polyadenylation of ribosomal RNA in human
cells
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, 34 (2006), pp

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