UNITED STATES v. O’HAGAN certiorari to the united states ...
Double Strand Breaks Can Initiate Gene Silencing and SIRT1-Dependent Onset of DNA Methylation in an...
-
Upload
linette-ellis -
Category
Documents
-
view
213 -
download
0
Transcript of Double Strand Breaks Can Initiate Gene Silencing and SIRT1-Dependent Onset of DNA Methylation in an...
![Page 1: Double Strand Breaks Can Initiate Gene Silencing and SIRT1-Dependent Onset of DNA Methylation in an Exogenous Promoter CpG Island Heather M. O’Hagan, Helai.](https://reader035.fdocuments.in/reader035/viewer/2022062714/56649cff5503460f949d0fdb/html5/thumbnails/1.jpg)
Double Strand Breaks Can Initiate Gene Silencing and SIRT1-Dependent Onset of
DNA Methylation in an Exogenous Promoter CpG Island
Heather M. O’Hagan, Helai P. Mohammad, Stephen B. Baylin
![Page 2: Double Strand Breaks Can Initiate Gene Silencing and SIRT1-Dependent Onset of DNA Methylation in an Exogenous Promoter CpG Island Heather M. O’Hagan, Helai.](https://reader035.fdocuments.in/reader035/viewer/2022062714/56649cff5503460f949d0fdb/html5/thumbnails/2.jpg)
Green et al. EMBO rep. 2002
ARR Model for DNA Repair
![Page 3: Double Strand Breaks Can Initiate Gene Silencing and SIRT1-Dependent Onset of DNA Methylation in an Exogenous Promoter CpG Island Heather M. O’Hagan, Helai.](https://reader035.fdocuments.in/reader035/viewer/2022062714/56649cff5503460f949d0fdb/html5/thumbnails/3.jpg)
Can the DNA Repair Process Lead to Aberrant Gene Silencing?
1) SIRT1 - protein/histone deacetylase that can be part of a PcG complex
2) EZH2 - HMT responsible for repressive histone marks, also in PcG complex
3) DNMT1 - involved in maintaining DNA methylation
4) DNMT3B - involved in de novo DNA methylation
• Tumor suppressor genes are often silenced in cancer cells.
• This silencing often occurs through epigenetic means such and chromatin modification and DNA methylation
Possible candidates for repair-induced silencing:
![Page 4: Double Strand Breaks Can Initiate Gene Silencing and SIRT1-Dependent Onset of DNA Methylation in an Exogenous Promoter CpG Island Heather M. O’Hagan, Helai.](https://reader035.fdocuments.in/reader035/viewer/2022062714/56649cff5503460f949d0fdb/html5/thumbnails/4.jpg)
Treatment with tetracycline induces a double strand break in the inserted E-cad promoter
![Page 5: Double Strand Breaks Can Initiate Gene Silencing and SIRT1-Dependent Onset of DNA Methylation in an Exogenous Promoter CpG Island Heather M. O’Hagan, Helai.](https://reader035.fdocuments.in/reader035/viewer/2022062714/56649cff5503460f949d0fdb/html5/thumbnails/5.jpg)
Treatment with tetracycline induces a double strand break in the inserted E-cad promoter
![Page 6: Double Strand Breaks Can Initiate Gene Silencing and SIRT1-Dependent Onset of DNA Methylation in an Exogenous Promoter CpG Island Heather M. O’Hagan, Helai.](https://reader035.fdocuments.in/reader035/viewer/2022062714/56649cff5503460f949d0fdb/html5/thumbnails/6.jpg)
DSB damage and/or repair induces the transient recruitment of SIRT1, DNMT1, and DNMT3B
![Page 7: Double Strand Breaks Can Initiate Gene Silencing and SIRT1-Dependent Onset of DNA Methylation in an Exogenous Promoter CpG Island Heather M. O’Hagan, Helai.](https://reader035.fdocuments.in/reader035/viewer/2022062714/56649cff5503460f949d0fdb/html5/thumbnails/7.jpg)
DSB damage and/or repair induces the transient recruitment of SIRT1, DNMT1, and DNMT3B
![Page 8: Double Strand Breaks Can Initiate Gene Silencing and SIRT1-Dependent Onset of DNA Methylation in an Exogenous Promoter CpG Island Heather M. O’Hagan, Helai.](https://reader035.fdocuments.in/reader035/viewer/2022062714/56649cff5503460f949d0fdb/html5/thumbnails/8.jpg)
Effects of knockdown of SIRT1 by siRNA
![Page 9: Double Strand Breaks Can Initiate Gene Silencing and SIRT1-Dependent Onset of DNA Methylation in an Exogenous Promoter CpG Island Heather M. O’Hagan, Helai.](https://reader035.fdocuments.in/reader035/viewer/2022062714/56649cff5503460f949d0fdb/html5/thumbnails/9.jpg)
Effects of knockdown of SIRT1 by siRNA
![Page 10: Double Strand Breaks Can Initiate Gene Silencing and SIRT1-Dependent Onset of DNA Methylation in an Exogenous Promoter CpG Island Heather M. O’Hagan, Helai.](https://reader035.fdocuments.in/reader035/viewer/2022062714/56649cff5503460f949d0fdb/html5/thumbnails/10.jpg)
Changes in enrichment of silencing proteins and chromatin marks with knockdown of SIRT1
![Page 11: Double Strand Breaks Can Initiate Gene Silencing and SIRT1-Dependent Onset of DNA Methylation in an Exogenous Promoter CpG Island Heather M. O’Hagan, Helai.](https://reader035.fdocuments.in/reader035/viewer/2022062714/56649cff5503460f949d0fdb/html5/thumbnails/11.jpg)
Changes in enrichment of silencing proteins and chromatin marks with knockdown of SIRT1
![Page 12: Double Strand Breaks Can Initiate Gene Silencing and SIRT1-Dependent Onset of DNA Methylation in an Exogenous Promoter CpG Island Heather M. O’Hagan, Helai.](https://reader035.fdocuments.in/reader035/viewer/2022062714/56649cff5503460f949d0fdb/html5/thumbnails/12.jpg)
Inducing a DSB in a promoter can lead to silencing and the seeding of methylation
![Page 13: Double Strand Breaks Can Initiate Gene Silencing and SIRT1-Dependent Onset of DNA Methylation in an Exogenous Promoter CpG Island Heather M. O’Hagan, Helai.](https://reader035.fdocuments.in/reader035/viewer/2022062714/56649cff5503460f949d0fdb/html5/thumbnails/13.jpg)
Inducing a DSB in a promoter can lead to silencing and the seeding of methylation
![Page 14: Double Strand Breaks Can Initiate Gene Silencing and SIRT1-Dependent Onset of DNA Methylation in an Exogenous Promoter CpG Island Heather M. O’Hagan, Helai.](https://reader035.fdocuments.in/reader035/viewer/2022062714/56649cff5503460f949d0fdb/html5/thumbnails/14.jpg)
Reduction of SIRT1 during DNA damage decreases the number of silent clones that have methylation
![Page 15: Double Strand Breaks Can Initiate Gene Silencing and SIRT1-Dependent Onset of DNA Methylation in an Exogenous Promoter CpG Island Heather M. O’Hagan, Helai.](https://reader035.fdocuments.in/reader035/viewer/2022062714/56649cff5503460f949d0fdb/html5/thumbnails/15.jpg)
Reduction of SIRT1 during DNA damage decreases the number of silent clones that have methylation
![Page 16: Double Strand Breaks Can Initiate Gene Silencing and SIRT1-Dependent Onset of DNA Methylation in an Exogenous Promoter CpG Island Heather M. O’Hagan, Helai.](https://reader035.fdocuments.in/reader035/viewer/2022062714/56649cff5503460f949d0fdb/html5/thumbnails/16.jpg)
Conclusions
• Silencing proteins can be recruited to the site near a double strand break
• Prolonged recruitment may lead to seeding and spreading of DNA methylation
• Supports a role for DNA damage in the epigenetic silencing of genes in tumors.
![Page 17: Double Strand Breaks Can Initiate Gene Silencing and SIRT1-Dependent Onset of DNA Methylation in an Exogenous Promoter CpG Island Heather M. O’Hagan, Helai.](https://reader035.fdocuments.in/reader035/viewer/2022062714/56649cff5503460f949d0fdb/html5/thumbnails/17.jpg)
Final questions or thoughts
• Are silencing proteins recruited during gene expression in order to rapidly turn genes off?– Could the same theory apply for genes being
expressed and not repaired?