Acetylation and Deacetylation of DNA Repair Proteins in Cancers

Abstract

Hundreds of DNA repair proteins coordinate together to remove the diverse damages for ensuring the genomic integrity and stability. The repair system is an extensive network mainly encompassing cell cycle arrest, chromatin remodeling, various repair pathways, and new DNA fragment synthesis. Acetylation on DNA repair proteins is a dynamic epigenetic modification orchestrated by lysine acetyltransferases (HATs) and lysine deacetylases (HDACs), which dramatically affects the protein functions through multiple mechanisms, such as regulation of DNA binding ability, protein activity, post-translational modification (PTM) crosstalk, and protein-protein interaction. Accumulating evidence has indicated that the aberrant acetylation of DNA repair proteins contributes to the dysfunction of DNA repair ability, the pathogenesis and progress of cancer, as well as the chemosensitivity of cancer cells. In the present scenario, targeting epigenetic therapy is being considered as a promising method at par with the conventional cancer therapeutic strategies. This present article provides an overview of the recent progress in the functions and mechanisms of acetylation on DNA repair proteins involved in five major repair pathways, which warrants the possibility of regulating acetylation on repair proteins as a therapeutic target in cancers.

Anticancer Therapy with HDAC Inhibitors: Mechanism-Based Combination Strategies and Future Perspectives

“…Thus, chromatin organization is of paramount importance for the integrity of the genome [ 141 , 142 , 143 ]. The next level, i.e., the HDAC-dependent regulation of the expression and function of the DNA repair machinery, is a highly complex issue, since virtually all types of DNA repair mechanisms are impacted by HDACs [ 140 , 144 ]. Thus, the in-depth discussion of DNA repair proteins that have been shown to be affected by HDAC inhibitors would go far beyond the scope of this review.…”

Human SIRT2 and SIRT3 deacetylases function in DNA homologous recombinational repair

“…However, we cannot rule out the other possibility that SIRT2 and SIRT3 might be involved in loading the RPA complex onto the ssDNA region at DSB sites. DSB end resection is catalyzed by several proteins, such as the MRE11‐NBS1‐RAD50 complex, EXO1, DNA2, BLM and CtIP (Katsuki et al., 2020), and various studies have shown that these proteins are acetylated (Balakrishnan et al., 2010; Li et al., 2020; Wang & Luo, 2017; Yuan et al., 2007). In addition, the chromatin structure is regulated by histone modifications, including acetylation, which influence the efficiency of DNA end resection reactions at DSB sites (Clouaire & Legube, 2015; Kollarovic et al., 2020).…”

“…Human SIRT1 deacetylates the p53 transcription factor (Luo et al., 2001; Vaziri et al., 2001), the XPA nucleotide excision repair protein (Fan & Luo, 2010) and the APE1 base excision repair protein (Yamamori et al., 2010). SIRT6 and SIRT7 regulate chromatin structure by changing histone modifications and recruiting chromatin remodelers to DSB sites (Li et al., 2020; Toiber et al., 2013; Vazquez et al., 2016), and SIRT6 also functions in base excision repair (BER) (Mostoslavsky et al., 2006).…”

Antagonistic relationship of NuA4 with the Non-Homologous End-Joining machinery at DNA damage sites

“…Furthermore, the Nej1-3KQ acetyl-mimic mutant also shows decreased binding to the C-terminal part of Mre11 compared to wild type and the 3KR mutant, which may affect its tethering activity (S5D Fig). Importantly, Nej1 phosphorylation in response to DNA damaging agents 58 In mammals, NHEJ core factor Ku70 is known to get acetylated by CBP which inhibits DNA repair and regulates Bax-mediated cell apoptosis (61,62). We tested if yeast Ku is also acetylated in yeast cells and if it could be a non-histone target of NuA4, along with Nej1.…”