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Aging-US: SIRT6 mono-ADP ribosylates KDM2A to locally increase H3K36me2

06-29-2020

The cover for issue 12 of Aging-US features "SIRT6 mono-ADP ribosylates KDM2A to locally increase H3K36me2 at DNA damage sites to inhibit transcription and promote repair" by Rezazadeh et al. and reported that when transcribed DNA is damaged, the transcription and DNA repair machinery must interact to ensure successful DNA repair.

Here the authors show that the SIRT6 protein enhances non-homologous end-joining DNA repair by transiently repressing transcription.

This results in transient suppression of transcription initiation by RNA polymerase II and the recruitment of NHEJ factors to DNA double-stranded breaks.

These data reveal a mechanism where SIRT6 mediates crosstalk between transcription and DNA repair machinery 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.

Dr. Andrei Seluanov and Dr. Vera Gorbunova from The Department of Biology at The University of Rochester said, "One of the most deleterious forms of DNA damage, DNA double-strand breaks (DSBs) can trigger cell death if left unrepaired."

Faulty DSB repair may lead to cancer and contribute to premature aging.

Figure 5. SIRT6 prevents collision between transcription and DSB repair machineries. Under basal conditions KDM2A demethylates H3K36 at transcription start site. Upon DNA damage SIRT6, is recruited to the DSB locus and mono-ADP ribosylates KDM2A leading to its displacement from chromatin. This leads to accumulation of H3K36me2 marks around the DSB site, which recruits HP1α and promotes deposition of H3K9me3 mark leading to local chromatin compaction. As a result, transcription is paused and DNA repair by NHEJ ensues.

DSBs are repaired by two main pathways: non-homologous end-joining, which operates throughout the cell cycle, and homologous recombination which is limited to S and G2 cell-cycle phases.

Histones, the basic protein units of chromatin, are subjected to modifications such as acetylation, phosphorylation, and ubiquitylation that alter the properties of chromatin and influence DNA repair.

Histone acetylation and methylation, together with the enzymes mediating their addition and removal, have also been implicated in the DDR. While the role of histone acetylation and methylation in transcriptional regulation is well established, their modes of action in DNA repair are less clear.

During NHEJ, ionizing radiation induces H3K36me2 by the DNA repair protein Metnase, a SET histone methyltransferase domain-containing protein, at DSB sites.

SIRT6 is a histone deacetylase, deacetylase, and mono-ADP ribosyl transferase involved in diverse processes including metabolism, transcription, and DNA repair.

The Seluanov/Gorbunova Research Team concluded in their Aging-US Research Paper that they demonstrate that SIRT6 promotes DNA repair of transcribed genes by preventing a collision between transcription and DNA repair by a novel mechanism involving mono-ADP ribosylation of KDM2A. This may represent a conserved mechanism of longevity as longevity associated genes are enriched for processes related to DNA repair.

Activating SIRT6 has been shown to extend lifespan, and coordination between transcription and DNA repair may be yet another SIRT6 function beneficial for genome maintenance and lifespan.

"The earliest retrospective study of the COVID-19 outbreak in Wuhan, China, published in the Lancet, was among one of the first clinical studies to identify older age as a significant risk factor for in-hospital mortality, suggesting that advanced chronological age may play an epidemiological role in patient clinical outcomes"

Full Text - https://doi.org/10.18632/aging.103567

Correspondence to: Andrei Seluanov email: andrei.seluanov@rochester.edu and Vera Gorbunova email: vera.gorbunova@rochester.edu

Keywords: SIRT6, DNA repair, transcription, genome stability, longevity

About Aging-US:

The mission of the journal is to understand the mechanisms surrounding aging and age-related diseases, including cancer as the main cause of death in the modern aged population.

The journal aims to promote 1) treatment of age-related diseases by slowing down aging, 2) validation of anti-aging drugs by treating age-related diseases, and 3) prevention of cancer by inhibiting aging. (Cancer and COVID-19 are age-related diseases.)

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