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Regulated Unproductive Splicing. Liana Lareau Brenner Group* *Labs aren’t carpeted. Groups are. Or so I’m told. Alternative Splicing. Genomic DNA Sequence. Transcription. pre-mRNA. Intron. Intron. Intron. Exon. Exon. Exon. Exon. Exon. RNA Processing. G m. AAAAA. G m. AAAAA.

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Regulated unproductive splicing

Regulated Unproductive Splicing

Liana Lareau

Brenner Group*

*Labs aren’t carpeted. Groups are. Or so I’m told.


Alternative splicing
Alternative Splicing

Genomic DNA Sequence

Transcription

pre-mRNA

Intron

Intron

Intron

Exon

Exon

Exon

Exon

Exon

RNA Processing

Gm

AAAAA

Gm

AAAAA

mRNA

mRNA




Inferred isoforms
Inferred Isoforms

0

10000

2000

4000

6000

8000

5970

Alternative isoforms

9527

All isoforms, including canonical

3557 genes with alternative spicing, from 12,000 mRNAs


Inferred isoforms1

Premature

stop codon

2078 (35 % of 5970)

Inferred Isoforms

0

10000

2000

4000

6000

8000

5970

Alternative isoforms

9527

All isoforms, including canonical


Nonsense mediated mrna decay
Nonsense-Mediated mRNA Decay

Translated normally

ORF

Gm

mRNA

AAAAAAAAA

Degraded by NMD

ORF

Gm

mRNA

AAAAAAAAA

>50 nt


Alternative splicing can yield isoforms differentially subjected to decay
Alternative Splicing Can Yield Isoforms Differentially Subjected to Decay

DNA

DNA

pre-mRNA

pre-mRNA

mRNA

mRNA

Nonsense

mediated

decay

Premature

termination

codon


Eukaryota
Eukaryota Subjected to Decay


Eukaryota1
Eukaryota Subjected to Decay

human, mouse,

fly

yeast


Eukaryote sequencing projects
Eukaryote sequencing projects Subjected to Decay

1

3

6

1

16

1

8

5


The players
The Players Subjected to Decay

Upf1aka RENT1 (human), SMG-2 (C. elegans)

Binds to downstream Upf2 and Upf3 during translation termination

Promotes mRNA decapping and degradation

Upf2aka SMG-3 (C. elegans)

Binds to Upf3 after nuclear export

Upf3aka SMG-4 (C. elegans)

Associates with exon junction complex in nucleus


Upf1 Subjected to Decay


Upf2 Subjected to Decay


Upf3 Subjected to Decay


Eukaryota2
Eukaryota Subjected to Decay

Plasmodium,

Cryptosporidium

human, mouse,

fly, mosquito,

worm

yeast, S. pombe,

Aspergillus, Neurospora


Upf3 yeast vs human
Upf3: Yeast vs. Human Subjected to Decay

BLAST results:

Score = 26.9 bits (58), Expect = 9.8

Identities = 30/131 (22%), Positives = 48/131 (36%), Gaps = 16/131 (12%)


transcriptional Subjected to Decay

regulation

Gene locus

transcription

pre-mRNA

productive

splicing

productive

mRNA

regulated

unproductive splicing

translation

Protein


ORF Subjected to Decay

SC35 pre-mRNA

SC35 Auto-regulation

Sureau et al. (2001) EMBO J20:1785-96


ORF Subjected to Decay

SC35 pre-mRNA

Gm

AAAAA

SC35 mRNA

SC35 Auto-regulation

Sureau et al. (2001) EMBO J20:1785-96


ORF Subjected to Decay

SC35 pre-mRNA

Gm

AAAAA

SC35 mRNA

SC35

SC35

protein

SC35 Auto-regulation

Sureau et al. (2001) EMBO J20:1785-96


ORF Subjected to Decay

SC35 pre-mRNA

Gm

AAAAA

SC35 mRNA

SC35

SC35

SC35

protein

SC35 pre-mRNA

SC35 Auto-regulation

Sureau et al. (2001) EMBO J20:1785-96


ORF Subjected to Decay

SC35 pre-mRNA

Gm

AAAAA

SC35 mRNA

SC35

SC35

SC35

protein

SC35 pre-mRNA

Gm

AAAAA

SC35 Auto-regulation

SC35 mRNA

(with premature termination codon)

Sureau et al. (2001) EMBO J20:1785-96


ORF Subjected to Decay

SC35 pre-mRNA

Gm

AAAAA

SC35 mRNA

SC35

SC35

SC35

protein

SC35 pre-mRNA

Gm

AAAAA

SC35 Auto-regulation

SC35 mRNA

(with premature termination codon)

Sureau et al. (2001) EMBO J20:1785-96


Sc35 auto regulation
SC35 Auto-regulation Subjected to Decay

SC35 Locus

transcription

SC35 pre-mRNA

alternative

splicing

splicing

Productive SC35 mRNA

translation

SC35 protein


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