Acetylation of BLM protein regulates its function in response to DNA damage

Wang, Yankun; Luo, Jianyuan

doi:10.1039/c7ra06666j

Cited by 5 publications

(4 citation statements)

References 43 publications

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“…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).…”

Section: Discussionmentioning

confidence: 99%

Human SIRT2 and SIRT3 deacetylases function in DNA homologous recombinational repair

Yasuda

Takizawa

et al. 2021

Genes to Cells

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SIRT2 and SIRT3 protein deacetylases maintain genome integrity and stability. However, their mechanisms for maintaining the genome remain unclear. To examine the roles of SIRT2 and SIRT3 in DSB repair, I‐SceI‐based GFP reporter assays for HR, single‐strand annealing (SSA) and nonhomologous end joining (NHEJ) repair were performed under SIRT2‐ or SIRT3‐depleted conditions. SIRT2 or SIRT3 depletion inhibited HR repair equally to RAD52 depletion, but did not affect SSA and NHEJ repairs. SIRT2 or SIRT3 depletion disturbed the recruitment of RAD51 to DSB sites, an essential step for RAD51‐dependent HR repair, but not directly through RAD52 deacetylation. SIRT2 or SIRT3 depletion decreased the colocalization of γH2AX foci with RPA1, and thus, they might be involved in initiating DSB end resection for the recruitment of RAD51 to DSB sites at an early step in HR repair. These results show the novel underlying mechanism of the SIRT2 and SIRT3 functions in HR for genome stability

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Section: Discussionmentioning

confidence: 99%

Human SIRT2 and SIRT3 deacetylases function in DNA homologous recombinational repair

Yasuda

Takizawa

et al. 2021

Genes to Cells

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“…Pif1's helicase core alone houses the seven conserved amino acid motifs common to this family where the direction of ssDNA translocation is determined, ATP hydrolysis, and ssDNA binding occur (65)(66)(67). Lysine acetylation of the BLM helicase is similarly spread across its different domains, allowing for regulation of its functions during DNA replication and the DNA damage response (27).…”

Section: Discussionmentioning

confidence: 99%

“…Acetylation of the ε-amino group on a lysine residue is one such PTM that has been studied in the context of modulating chromatin architecture for many decades (23)(24)(25). However, many non-histone proteins are also modified by acetylation, including replication/repair-associated helicases such as Dna2 (26), BLM (27), and WRN (28).…”

Section: Introductionmentioning

confidence: 99%

Lysine acetylation regulates the activity of nuclear Pif1

Ononye

Sausen

Balakrishnan

et al. 2020

Journal of Biological Chemistry

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In S. cerevisiae, the Pif1 helicase functions in both nuclear and mitochondrial DNA replication and repair processes, preferentially unwinding RNA-DNA hybrids and resolving G-quadruplex structures. We sought to determine how the various activities of Pif1 are regulated in vivo. Here, we report lysine acetylation of nuclear Pif1 and demonstrate that it influences both Pif1’s cellular roles and core biochemical activities. Using Pif1 overexpression toxicity assays, we determined that the acetyltransferase NuA4 and deacetylase Rpd3 are primarily responsible for the dynamic acetylation of nuclear Pif1. Mass spectrometry analysis revealed that Pif1 was modified in several domains throughout the protein’s sequence on the N-terminus (K118, K129), helicase domain (K525, K639, K725), and C-terminus (K800). Acetylation of Pif1 exacerbated its overexpression toxicity phenotype, which was alleviated upon deletion of its N-terminus. Biochemical assays demonstrated that acetylation of Pif1 stimulated its helicase, ATPase, and DNA binding activities while maintaining its substrate preferences. Limited proteolysis assays indicate that acetylation of Pif1 induces a conformational change that may account for its altered enzymatic properties. We propose that acetylation is involved in regulating of Pif1 activities, influencing a multitude of DNA transactions vital to the maintenance of genome integrity.

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“…Acetylation of the εamino group on a lysine residue is one such PTM that has been studied in the context of modulating chromatin architecture for many decades [23][24][25]. However, many non-histone proteins are also modified by acetylation, including replication/repair-associated helicases such as Dna2 [26], BLM [27], and WRN [28].…”

mentioning

confidence: 99%

Nuclear Pif1 is Post Translationally Modified and Regulated by Lysine Acetylation

Ononye

Sausen

Balakrishnan

et al. 2020

Preprint

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ABSTRACTIn S. cerevisiae, the Pif1 helicase functions to impact both nuclear and mitochondrial DNA replication and repair processes. Pif1 is a 5’-3’ helicase, which preferentially unwinds RNA-DNA hybrids and resolves G-quadruplex structures. Further, regulation of Pif1 by phosphorylation negatively impacts its interaction with telomerase during double strand break repair. Here, we report that in addition to phosphorylation, Pif1 is also modified by lysine acetylation, which influences both its cellular and core biochemical activities. Using Pif1 overexpression toxicity assays, we determined that the acetyltransferase NuA4 (Esa1) and deacetylase Rpd3 are primarily responsible for dynamically acetylating nuclear Pif1. Mass spectrometry analysis revealed that Pif1 was modified throughout the protein’s sequence on the N-terminus (K118, K129), helicase domain (K525, K639, K725), and C-terminus (K800). Acetylation of Pif1 exacerbated its overexpression toxicity phenotype, which was alleviated upon deletion of its N-terminus. Biochemical assays demonstrated that acetylation of Pif1 stimulated its helicase activity, while maintaining its substrate preferences. Additionally, both the ATPase and DNA binding activities of Pif1 were stimulated upon acetylation. Limited proteolysis assays indicate that acetylation of Pif1 induces a conformational change that may account for its altered enzymatic properties. We propose an acetylation-based model for the regulation of Pif1 activities, addressing how this post translational modification can influence its role as a key player in a multitude of DNA transactions vital to the maintenance of genome integrity.

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Acetylation of BLM protein regulates its function in response to DNA damage

Cited by 5 publications

References 43 publications

Human SIRT2 and SIRT3 deacetylases function in DNA homologous recombinational repair

Human SIRT2 and SIRT3 deacetylases function in DNA homologous recombinational repair

Lysine acetylation regulates the activity of nuclear Pif1

Nuclear Pif1 is Post Translationally Modified and Regulated by Lysine Acetylation

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