Hwang, BJ and Jin, J and Gao, Y and Shi, G and Madabushi, A and Yan, A and Guan, X and Zalzman, M and Nakajima, S and Lan, L and Lu, AL
(2015)
SIRT6 protein deacetylase interacts with MYH DNA glycosylase, APE1 endonuclease, and Rad9-Rad1-Hus1 checkpoint clamp.
BMC Molecular Biology, 16 (1).
Abstract
Background: SIRT6, a member of the NAD+-dependent histone/protein deacetylase family, regulates genomic stability, metabolism, and lifespan. MYH glycosylase and APE1 are two base excision repair (BER) enzymes involved in mutation avoidance from oxidative DNA damage. Rad9-Rad1-Hus1 (9-1-1) checkpoint clamp promotes cell cycle checkpoint signaling and DNA repair. BER is coordinated with the checkpoint machinery and requires chromatin remodeling for efficient repair. SIRT6 is involved in DNA double-strand break repair and has been implicated in BER. Here we investigate the direct physical and functional interactions between SIRT6 and BER enzymes. Results: We show that SIRT6 interacts with and stimulates MYH glycosylase and APE1. In addition, SIRT6 interacts with the 9-1-1 checkpoint clamp. These interactions are enhanced following oxidative stress. The interdomain connector of MYH is important for interactions with SIRT6, APE1, and 9-1-1. Mutagenesis studies indicate that SIRT6, APE1, and Hus1 bind overlapping but different sequence motifs on MYH. However, there is no competition of APE1, Hus1, or SIRT6 binding to MYH. Rather, one MYH partner enhances the association of the other two partners to MYH. Moreover, APE1 and Hus1 act together to stabilize the MYH/SIRT6 complex. Within human cells, MYH and SIRT6 are efficiently recruited to confined oxidative DNA damage sites within transcriptionally active chromatin, but not within repressive chromatin. In addition, Myh foci induced by oxidative stress and Sirt6 depletion are frequently localized on mouse telomeres. Conclusions: Although SIRT6, APE1, and 9-1-1 bind to the interdomain connector of MYH, they do not compete for MYH association. Our findings indicate that SIRT6 forms a complex with MYH, APE1, and 9-1-1 to maintain genomic and telomeric integrity in mammalian cells.
Share
Citation/Export: |
|
Social Networking: |
|
Details
Item Type: |
Article
|
Status: |
Published |
Creators/Authors: |
Creators | Email | Pitt Username | ORCID |
---|
Hwang, BJ | | | | Jin, J | | | | Gao, Y | | | | Shi, G | | | | Madabushi, A | | | | Yan, A | | | | Guan, X | | | | Zalzman, M | | | | Nakajima, S | san48@pitt.edu | SAN48 | | Lan, L | lil64@pitt.edu | LIL64 | | Lu, AL | | | |
|
Centers: |
Other Centers, Institutes, Offices, or Units > Pittsburgh Cancer Institute |
Date: |
11 June 2015 |
Date Type: |
Publication |
Journal or Publication Title: |
BMC Molecular Biology |
Volume: |
16 |
Number: |
1 |
DOI or Unique Handle: |
10.1186/s12867-015-0041-9 |
Schools and Programs: |
School of Medicine > Medicine School of Medicine > Microbiology and Molecular Genetics |
Refereed: |
Yes |
Date Deposited: |
17 Aug 2016 13:24 |
Last Modified: |
22 Jun 2021 13:55 |
URI: |
http://d-scholarship.pitt.edu/id/eprint/29245 |
Metrics
Monthly Views for the past 3 years
Plum Analytics
Altmetric.com
Actions (login required)
|
View Item |