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Double Strand Breaks Can Initiate Gene Silencing and SIRT1-Dependent Onset of DNA Methylation in an Exogenous Promoter

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. ARR Model for DNA Repair. Green et al. EMBO rep. 2002.

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Double Strand Breaks Can Initiate Gene Silencing and SIRT1-Dependent Onset of DNA Methylation in an Exogenous Promoter

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  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 P. Mohammad, Stephen B. Baylin

  2. ARR Model for DNA Repair Green et al. EMBO rep. 2002

  3. Can the DNA Repair Process Lead to Aberrant Gene Silencing? • 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: 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

  4. Treatment with tetracycline induces a double strand break in the inserted E-cad promoter

  5. Treatment with tetracycline induces a double strand break in the inserted E-cad promoter

  6. DSB damage and/or repair induces the transient recruitment of SIRT1, DNMT1, and DNMT3B

  7. DSB damage and/or repair induces the transient recruitment of SIRT1, DNMT1, and DNMT3B

  8. Effects of knockdown of SIRT1 by siRNA

  9. Effects of knockdown of SIRT1 by siRNA

  10. Changes in enrichment of silencing proteins and chromatin marks with knockdown of SIRT1

  11. Changes in enrichment of silencing proteins and chromatin marks with knockdown of SIRT1

  12. Inducing a DSB in a promoter can lead to silencing and the seeding of methylation

  13. Inducing a DSB in a promoter can lead to silencing and the seeding of methylation

  14. Reduction of SIRT1 during DNA damage decreases the number of silent clones that have methylation

  15. Reduction of SIRT1 during DNA damage decreases the number of silent clones that have methylation

  16. 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.

  17. 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?

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