Priority Research Paper Volume 12, Issue 18 pp 17761—17785
An ordered assembly of MYH glycosylase, SIRT6 protein deacetylase, and Rad9-Rad1-Hus1 checkpoint clamp at oxidatively damaged telomeres
- 1 Massachusetts General Hospital Cancer Center, Department of Radiation Oncology, Harvard Medical School, Charlestown, MA 02129, USA
- 2 Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- 3 Nathan Schnaper Intern Program in Translational Cancer Research, University of Maryland School of Medicine, 108 North Greene Street, Baltimore, MD 21201, USA
- 4 Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA
Received: May 12, 2020 Accepted: August 7, 2020 Published: September 29, 2020
https://doi.org/10.18632/aging.103934How to Cite
Copyright: © 2020 Tan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
In the base excision repair pathway, MYH/MUTYH DNA glycosylase prevents mutations by removing adenine mispaired with 8-oxoG, a frequent oxidative lesion. MYH glycosylase activity is enhanced by Rad9-Rad1-Hus1 (9-1-1) checkpoint clamp and SIRT6 histone/protein deacetylase. Here, we show that MYH, SIRT6, and 9-1-1 are recruited to confined oxidatively damaged regions on telomeres in mammalian cells. Using different knockout cells, we show that SIRT6 responds to damaged telomeres very early, and then recruits MYH and Hus1 following oxidative stress. However, the recruitment of Hus1 to damaged telomeres is partially dependent on SIRT6. The catalytic activities of SIRT6 are not important for SIRT6 response but are essential for MYH recruitment to damaged telomeres. Compared to wild-type MYH, the recruitment of hMYHV315A mutant (defective in both SIRT6 and Hus1 interactions), but not hMYHQ324H mutant (defective in Hus1 interaction only), to damaged telomeres is severely reduced. The formation of MYH/SIRT6/9-1-1 complex is of biological significance as interrupting their interactions can increase cell’s sensitivity to H2O2 and/or elevate cellular 8-oxoG levels after H2O2 treatment. Our results establish that SIRT6 acts as an early sensor of BER enzymes and both SIRT6 and 9-1-1 serve critical roles in DNA repair to maintain telomere integrity.