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Protein degradation pathways regulate the functions of helicases in the DNA damage response and maintenance of genomic stability.

Sommers JA, Suhasini AN, Brosh RM - Biomolecules (2015)

Bottom Line: Degradation of helicases or helicase-like proteins, often mediated by ubiquitin-proteasomal pathways, plays important regulatory roles in cellular mechanisms that respond to DNA damage or replication stress.Stability of the Werner syndrome helicase-nuclease (WRN) involved in the replication stress response is regulated by its acetylation.Collectively, these studies demonstrate that helicases can be targeted for degradation to maintain genome homeostasis.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, NIH Biomedical Research Center, 251 Bayview Blvd, Baltimore, MD 21224, USA. sommersj@mail.nih.gov.

ABSTRACT
Degradation of helicases or helicase-like proteins, often mediated by ubiquitin-proteasomal pathways, plays important regulatory roles in cellular mechanisms that respond to DNA damage or replication stress. The Bloom's syndrome helicase (BLM) provides an example of how helicase degradation pathways, regulated by post-translational modifications and protein interactions with components of the Fanconi Anemia (FA) interstrand cross-link (ICL) repair pathway, influence cell cycle checkpoints, DNA repair, and replication restart. The FANCM DNA translocase can be targeted by checkpoint kinases that exert dramatic effects on FANCM stability and chromosomal integrity. Other work provides evidence that degradation of the F-box DNA helicase (FBH1) helps to balance translesion synthesis (TLS) and homologous recombination (HR) repair at blocked replication forks. Degradation of the helicase-like transcription factor (HLTF), a DNA translocase and ubiquitylating enzyme, influences the choice of post replication repair (PRR) pathway. Stability of the Werner syndrome helicase-nuclease (WRN) involved in the replication stress response is regulated by its acetylation. Turning to transcription, stability of the Cockayne Syndrome Group B DNA translocase (CSB) implicated in transcription-coupled repair (TCR) is regulated by a CSA ubiquitin ligase complex enabling recovery of RNA synthesis. Collectively, these studies demonstrate that helicases can be targeted for degradation to maintain genome homeostasis.

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Werner syndrome helicase-nuclease (WRN) acetylation affects its stability, catalytic functions, and subcellular localization. See text for details.
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biomolecules-05-00590-f010: Werner syndrome helicase-nuclease (WRN) acetylation affects its stability, catalytic functions, and subcellular localization. See text for details.

Mentions: The WRN gene, mutated in the premature aging disorder Werner syndrome, encodes a protein with both DNA helicase and exonuclease activities (for review, see [66]). Work from the Orren and Luo laboratories showed that WRN can be targeted for acetylation by the acetyltransferases CBP and p300 which down-regulates its catalytic functions and affects its subcellular localization [67] (Figure 10). WRN acetylation at six lysine residues also increases its protein stability, whereas deacetylation of WRN by the sirtuin SIRT1 destabilizes WRN [68]. WRN stability is influenced by the ubiquitin pathway, which is negatively regulated when WRN is acetylated. After cellular exposure to the DNA cross-linking agent MMC, WRN is markedly acetylated leading to its stabilization. Cells expressing a WRN variant that is mutated at the six lysine residues thereby blocking its acetylation are hypersensitive to MMC, suggesting that an important aspect of WRN’s role in the DNA damage response is its regulation by acetylation which prevents its proteolytic degradation via a ubiquitin-proteasome pathway. Thus WRN acetylation and deacetylation may serve as a switch during DNA damage conditions that influences WRN catalytic function or its own degradation which in turn alters its role at stalled replication forks or sites of DNA damage [69]. In the future, it will be valuable to assess if certain histone deacetylase (HDAC) inhibitors currently used in the clinic might affect the acetyltransferase that modifies WRN as it is known that this class of compounds can alter the acetylation state and function of non-histone proteins as well as their traditional histone targets [70,71,72]. Given that certain HDAC inhibitors are approved or in clinical trials for cancer treatment, it will be informative to assess if WRN-dependent pathways are involved in anti-proliferation. This may be relevant to the development of WRN helicase inhibitors for anti-cancer therapy [73]. For example, a small molecule WRN helicase inhibitor that sensitizes FA-deficient cancer cells to MMC has implications for chemotherapy strategies [74,75].


Protein degradation pathways regulate the functions of helicases in the DNA damage response and maintenance of genomic stability.

Sommers JA, Suhasini AN, Brosh RM - Biomolecules (2015)

Werner syndrome helicase-nuclease (WRN) acetylation affects its stability, catalytic functions, and subcellular localization. See text for details.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496686&req=5

biomolecules-05-00590-f010: Werner syndrome helicase-nuclease (WRN) acetylation affects its stability, catalytic functions, and subcellular localization. See text for details.
Mentions: The WRN gene, mutated in the premature aging disorder Werner syndrome, encodes a protein with both DNA helicase and exonuclease activities (for review, see [66]). Work from the Orren and Luo laboratories showed that WRN can be targeted for acetylation by the acetyltransferases CBP and p300 which down-regulates its catalytic functions and affects its subcellular localization [67] (Figure 10). WRN acetylation at six lysine residues also increases its protein stability, whereas deacetylation of WRN by the sirtuin SIRT1 destabilizes WRN [68]. WRN stability is influenced by the ubiquitin pathway, which is negatively regulated when WRN is acetylated. After cellular exposure to the DNA cross-linking agent MMC, WRN is markedly acetylated leading to its stabilization. Cells expressing a WRN variant that is mutated at the six lysine residues thereby blocking its acetylation are hypersensitive to MMC, suggesting that an important aspect of WRN’s role in the DNA damage response is its regulation by acetylation which prevents its proteolytic degradation via a ubiquitin-proteasome pathway. Thus WRN acetylation and deacetylation may serve as a switch during DNA damage conditions that influences WRN catalytic function or its own degradation which in turn alters its role at stalled replication forks or sites of DNA damage [69]. In the future, it will be valuable to assess if certain histone deacetylase (HDAC) inhibitors currently used in the clinic might affect the acetyltransferase that modifies WRN as it is known that this class of compounds can alter the acetylation state and function of non-histone proteins as well as their traditional histone targets [70,71,72]. Given that certain HDAC inhibitors are approved or in clinical trials for cancer treatment, it will be informative to assess if WRN-dependent pathways are involved in anti-proliferation. This may be relevant to the development of WRN helicase inhibitors for anti-cancer therapy [73]. For example, a small molecule WRN helicase inhibitor that sensitizes FA-deficient cancer cells to MMC has implications for chemotherapy strategies [74,75].

Bottom Line: Degradation of helicases or helicase-like proteins, often mediated by ubiquitin-proteasomal pathways, plays important regulatory roles in cellular mechanisms that respond to DNA damage or replication stress.Stability of the Werner syndrome helicase-nuclease (WRN) involved in the replication stress response is regulated by its acetylation.Collectively, these studies demonstrate that helicases can be targeted for degradation to maintain genome homeostasis.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, NIH Biomedical Research Center, 251 Bayview Blvd, Baltimore, MD 21224, USA. sommersj@mail.nih.gov.

ABSTRACT
Degradation of helicases or helicase-like proteins, often mediated by ubiquitin-proteasomal pathways, plays important regulatory roles in cellular mechanisms that respond to DNA damage or replication stress. The Bloom's syndrome helicase (BLM) provides an example of how helicase degradation pathways, regulated by post-translational modifications and protein interactions with components of the Fanconi Anemia (FA) interstrand cross-link (ICL) repair pathway, influence cell cycle checkpoints, DNA repair, and replication restart. The FANCM DNA translocase can be targeted by checkpoint kinases that exert dramatic effects on FANCM stability and chromosomal integrity. Other work provides evidence that degradation of the F-box DNA helicase (FBH1) helps to balance translesion synthesis (TLS) and homologous recombination (HR) repair at blocked replication forks. Degradation of the helicase-like transcription factor (HLTF), a DNA translocase and ubiquitylating enzyme, influences the choice of post replication repair (PRR) pathway. Stability of the Werner syndrome helicase-nuclease (WRN) involved in the replication stress response is regulated by its acetylation. Turning to transcription, stability of the Cockayne Syndrome Group B DNA translocase (CSB) implicated in transcription-coupled repair (TCR) is regulated by a CSA ubiquitin ligase complex enabling recovery of RNA synthesis. Collectively, these studies demonstrate that helicases can be targeted for degradation to maintain genome homeostasis.

Show MeSH
Related in: MedlinePlus