SIRT6 mono-ADP ribosylates KDM2A to locally increase H3K36me2 at DNA damage sites to inhibit transcription and promote repair
- 25 June 2020
- journal article
- research article
- Published by Impact Journals, LLC in Aging
- Vol. 12 (12), 11165-11184
- https://doi.org/10.18632/aging.103567
Abstract
When transcribed DNA is damaged, the transcription and DNA repair machineries must interact to ensure successful DNA repair. The mechanisms of this interaction in the context of chromatin are still being elucidated. Here we show that the SIRT6 protein enhances non-homologous end joining (NHEJ) DNA repair by transiently repressing transcription. Specifically, SIRT6 mono-ADP ribosylates the lysine demethylase JHDM1A/KDM2A leading to rapid displacement of KDM2A from chromatin, resulting in increased H3K36me2 levels. Furthermore, we found that through HP1a binding, H3K36me2 promotes subsequent H3K9 tri-methylation. This results in transient suppression of transcription initiation by RNA polymerase II and recruitment of NHEJ factors to DNA double-stranded breaks (DSBs). These data reveal a mechanism where SIRT6 mediates a crosstalk between transcription and DNA repair machineries to promote DNA repair. SIRT6 functions in multiple pathways related to aging, and its novel function coordinating DNA repair and transcription is yet another way by which SIRT6 promotes genome stability and longevity.Keywords
This publication has 62 references indexed in Scilit:
- Reanalysis of phosphoproteomics data uncovers ADP-ribosylation sitesNature Methods, 2012
- Dynamics and Memory of Heterochromatin in Living CellsCell, 2012
- Proteomic Investigations Reveal a Role for RNA Processing Factor THRAP3 in the DNA Damage ResponseMolecular Cell, 2012
- The DNA Damage Response: Making It Safe to Play with KnivesMolecular Cell, 2010
- Human HDAC1 and HDAC2 function in the DNA-damage response to promote DNA nonhomologous end-joiningNature Structural & Molecular Biology, 2010
- ATM-Dependent Chromatin Changes Silence Transcription In cis to DNA Double-Strand BreaksCell, 2010
- CpG Islands Recruit a Histone H3 Lysine 36 DemethylaseMolecular Cell, 2010
- CpG islands influence chromatin structure via the CpG-binding protein Cfp1Nature, 2010
- Enzymatic and structural insights for substrate specificity of a family of jumonji histone lysine demethylasesNature Structural & Molecular Biology, 2009
- The SCX/IMAC enrichment approach for global phosphorylation analysis by mass spectrometryNature Protocols, 2008