•Homework #2 is posted and due 10/17

•Exam key is posted

Altering DNA’s Shape can Alter Gene Expression

How is class going?

1. The speed of lecture is:1= too slow – 5= too fast

2. After lecture I understand the material:1= barely – 5= very well

3. Class is enjoyable/interesting:1= no – 5= yes

4. The grade that I think I earned on exam 1=0–100

• Overview of transcriptional regulation

Figure 11-2

Fig 11.2

Mutations in the promoter show critical nucleotides

Fig 11.4

Fig 16.1

Gene Expression is controlled at all of these steps:•DNA packaging•Transcription•RNA processing and transport•RNA degradation•Translation•Post-translational

Different levels of DNA packaging Fig 11.10

Tightly packaged DNA is unavailable. DNA packaging changes as the need for different genes changes.

Fig 11.12

Histones can be post-translationally modified, which affects their abililty to bind DNA.

Acetylation (-COCH3): post-translational modifications of the histones loosen DNA binding

Acetylation of histones (-COCH3) causes a loosening of the DNA/histone bond…unpackaging the DNA.

Four-stranded DNA: cancer, gene regulation and drug developmentby Julian Leon HuppertPhilosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering SciencesTriennial Issue of 'Chemistry and Engineering’DOI: 10.1098/rsta.2007.0011Published: September 13, 2007

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4 strand DNA Fig 1

Four-stranded DNA forms between sequences of guanines…G-quadruplexes

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are needed to see this picture.

4 strand DNA Fig 1

Four-stranded DNA forms between sequences of guanines…G-quadruplexes

QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.

4 strand DNA Fig 2

The G-quadruplexes can form from 4, 2, or 1 DNA strand.

Fig 7.11

During DNA replication, the ends of the DNA are not completely copied.

Telomeres are non-gene DNA at the ends of DNA strands.

Telomeres are shortened during DNA replication.

Fig 7.26

Telomeres can be lengthened by telomerase.

The telomeric cap structure is one place where G-quadruplexes can be found

Telomeres are non-gene DNA at the ends of DNA strands.

Short telomeres will cause cells to stop replicating or cell death.

The critical size is unknown.

Drugs that can block the action of telomerase, by binding the G-quadruplexes, are being

investigated to treat cancer.

Fig 11.3

Eukaryotic promoters often contain G-rich areas

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4 strand DNA Fig 5

G-quadruplex in promoters

If the promoter is defined as 1 kbase upstream of the transcription start site:•Quadruplex motifs are significantly overrepresented relative to the rest of the genome, by almost an order of magnitude.

•almost half of all known genes have a putative quadruplex-forming motif

•By comparison, the TATA box motif—probably the best-known regulatory motif and a staple of undergraduate textbooks—is found in only approximately 10% of genes.Four-stranded DNA: cancer, gene regulation and drug development by Julian Leon Huppert in Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences Triennial Issue of 'Chemistry and Engineering’ DOI: 10.1098/rsta.2007.0011 Published: September 13, 2007

Four-stranded DNA: cancer, gene regulation and drug development by Julian Leon Huppert in Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences Triennial Issue of 'Chemistry and Engineering’ DOI: 10.1098/rsta.2007.0011 Published: September 13, 2007

Oncogenes, the genes involved in cancer, are especially rich in potentially regulatory quadruplexes—69% of them have such motifs

Werner syndrome, which causes premature aging, is caused by the lack of a helicase that binds to G-quadruplexes.

Four-stranded DNA: cancer, gene regulation and drug development by Julian Leon Huppert in Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences Triennial Issue of 'Chemistry and Engineering’ DOI: 10.1098/rsta.2007.0011 Published: September 13, 2007

G-quadruplex ligands

G-quadruplex

BRACO-19

TMPyP4

telomestatin

4 strandDNAFig 6

Down regulates telomerase and some oncogene transcription

Specifically binds to telomeres, naturally occurring in Streptomyces anulatus

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4 strand DNA Fig 7

Model of specific G-quadruplex ligand binding to G-quadruplex and a specific DNA sequence

•Homework #2 is posted and due 10/17

•Exam key is posted

Altering DNA’s Shape can Alter Gene Expression