Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
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 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 Treatment with tetracycline induces a double strand break in the inserted E-cad promoter Treatment with tetracycline induces a double strand break in the inserted E-cad promoter DSB damage and/or repair induces the transient recruitment of SIRT1, DNMT1, and DNMT3B DSB damage and/or repair induces the transient recruitment of SIRT1, DNMT1, and DNMT3B Effects of knockdown of SIRT1 by siRNA Effects of knockdown of SIRT1 by siRNA Changes in enrichment of silencing proteins and chromatin marks with knockdown of SIRT1 Changes in enrichment of silencing proteins and chromatin marks with knockdown of SIRT1 Inducing a DSB in a promoter can lead to silencing and the seeding of methylation Inducing a DSB in a promoter can lead to silencing and the seeding of methylation Reduction of SIRT1 during DNA damage decreases the number of silent clones that have methylation Reduction of SIRT1 during DNA damage decreases the number of silent clones that have methylation 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. 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?