An ATM-Dependent Transcriptional Silencing Program is Transmitted Through Chromatin in Cis to DNA Double Strand Breaks

By N. Shanbhag, Ilona U. Rafalska-Metcalf, Carlo Balane-Bolivar, S. Janicki, R. Greenberg. Cell, 2010

707 citations recorded by the source corpus.

Summary DNA double strand breaks (DSBs) initiate extensive local and global alterations in chromatin structure, many of which depend on the ATM kinase. Histone H2A ubiquitylation (uH2A) on chromatin surrounding DSBs is one example, thought to be important for recruitment of repair proteins. uH2A is also implicated in transcriptional repression; an intriguing yet untested hypothesis is that this function is conserved in the context of DSBs. Using a novel reporter that allows for visualization of repair protein recruitment and local transcription in single cells, we describe an ATM-dependent transcriptional silencing program in cis to DSBs. ATM prevents RNA polymerase II elongation dependent chromatin decondensation at regions distal to DSBs. Silencing is partially dependent on E3 ubiquitin ligases RNF8 and RNF168, while reversal of silencing relies on the uH2A deubiquitylating enzyme USP16. These findings give insight into the role of post-translational modifications in mediating cross talk between diverse processes occurring on chromatin.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/2186d9441634115d485446af3bae2ed78a000ebe

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In Molecular Biology

1. Stephen P. Jackson
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Citations in the corpus

• More than just a focus: The chromatin response to DNA damage and its role in genome integrity maintenance (2011, background): “In contrast to the polycomb activities, the RNF8–RNF168 pathway can extend H2A-associated ubiquitin chains and recent work revealed that this indeed contributes to local transcriptional silencing by inhibiting elongation of RNA polymerase II (ref”
• DNA damage and its links to neurodegeneration (2014, positive): “Meanwhile, several groups working in dividing cells reported that SIRT1 is essential for the recruitment of NBS1 and RAD51 to the sites of DNA DSBs and that HDAC1 plays an Neuron.”
• Playing the end game: DNA double-strand break repair pathway choice. (2012, background): “Indeed, transcriptional silencing in close proximity to DSBs requires the RNF8/168dependent histone ubiquitylation that also coordinates 53BP1 recruitment (Shanbhag et al., 2010).”
• RNF168 ubiquitinates K13-15 on H2A/H2AX to drive DNA damage signaling. (2012, background): “On the one hand, monoubiquitination of K119 could be important for the transcriptional silencing of the regions around the damage, as previously suggested (Chagraoui et al., 2011; Shanbhag et al., 2010).”
• Small molecule-induced DNA damage identifies alternative DNA structures in human genes (2012, positive): “Pyridostatin alters mRNA levels of damaged genes As local DNA damage within a genomic locus can trigger transcriptional inhibition in cis”
• The DNA Damage Response: Making it safe to play with knives (2010, background): “Recent observations have suggested that DSB formation leads to ATM-dependent repression of transcription in the vicinity of the DSB (Shanbhag et al., 2010).”
• Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications. (2011, background): “In this regard, DNA methylation and histone modifications—including deacetylation, methylation, and ubiquitylation at sites of DNA breaks—have been proposed to contribute to silencing of damaged chromatin (O’Hagan et al. 2008; Shanbhag et al. 2010).”