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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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CSA-associated ubiquitin ligase insures CSB degradation enabling RNA synthesis recovery in the transcription-coupled repair pathway. See text for details.
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biomolecules-05-00590-f012: CSA-associated ubiquitin ligase insures CSB degradation enabling RNA synthesis recovery in the transcription-coupled repair pathway. See text for details.

Mentions: The DNA repair disorder Cockayne syndrome (CS) is an autosomal recessive disease caused by mutations in the CSA or CSB genes [84]. The CSA gene encodes a WD-repeat protein that is associated with Cullin 4A (CUL4A) E3 ubiquitin ligase. The CSB gene encodes a SWI2/SNF2 DNA-dependent ATPase that can remodel chromatin. Cells derived from CSA or CSB patients are UV-sensitive and defective in transcription-coupled repair (TCR), resulting in delayed cover of RNA synthesis after UV-induced DNA damage. Understanding the precise molecular role(s) of CSA and CSB in TCR has posed a daunting challenge in the field. It is generally believed that the initiating signal for TCR is a stalled RNA Polymerase II at the lesion, followed by recruitment of CSA and CSB which are required for further assembly of nucleotide excision repair (NER) proteins responsible for removal of the lesion [84]. Groisman et al. discovered a functional relationship between CSA and CSB with the demonstration that CSB is degraded by an E3 ubiquitin ligase complex that contains CSA [28] (Figure 12). Normally, CSB is degraded within 4 h post UV irradiation in a proteasome-dependent manner; however, in CSA-deficient fibroblasts, CSB level is unaffected after UV exposure. In vitro studies demonstrated that the CSA-associated E3 ligase complex directly ubiquitylates CSB. The authors next wanted to assess the biological importance of CSB degradation post UV treatment. Building on an earlier observation that cellular exposure to a proteasome inhibitor suppresses RNA synthesis recovery [85], Groisman et al. determined that CSB persists in the CSA complex in MG132-treated cells and that the residual RNA synthesis recovery in CS-A or CS-B cells is insensitive to MG132 [28]. Thus, CSB degradation mediated by the CSA E3 ubiquitin ligase complex is necessary to remove CSB from the DNA after it has fulfilled its role to recruit NER proteins so that transcription can recover at the repaired site. In a more recent study, evidence was presented that BRCA1 poly-ubiquitylates CSB protein leading to CSB degradation and resulting in improved UV resistance, suggesting a pathway in addition to the CSA-dependent one [29].


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)

CSA-associated ubiquitin ligase insures CSB degradation enabling RNA synthesis recovery in the transcription-coupled repair pathway. See text for details.
© Copyright Policy
Related In: Results  -  Collection

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

biomolecules-05-00590-f012: CSA-associated ubiquitin ligase insures CSB degradation enabling RNA synthesis recovery in the transcription-coupled repair pathway. See text for details.
Mentions: The DNA repair disorder Cockayne syndrome (CS) is an autosomal recessive disease caused by mutations in the CSA or CSB genes [84]. The CSA gene encodes a WD-repeat protein that is associated with Cullin 4A (CUL4A) E3 ubiquitin ligase. The CSB gene encodes a SWI2/SNF2 DNA-dependent ATPase that can remodel chromatin. Cells derived from CSA or CSB patients are UV-sensitive and defective in transcription-coupled repair (TCR), resulting in delayed cover of RNA synthesis after UV-induced DNA damage. Understanding the precise molecular role(s) of CSA and CSB in TCR has posed a daunting challenge in the field. It is generally believed that the initiating signal for TCR is a stalled RNA Polymerase II at the lesion, followed by recruitment of CSA and CSB which are required for further assembly of nucleotide excision repair (NER) proteins responsible for removal of the lesion [84]. Groisman et al. discovered a functional relationship between CSA and CSB with the demonstration that CSB is degraded by an E3 ubiquitin ligase complex that contains CSA [28] (Figure 12). Normally, CSB is degraded within 4 h post UV irradiation in a proteasome-dependent manner; however, in CSA-deficient fibroblasts, CSB level is unaffected after UV exposure. In vitro studies demonstrated that the CSA-associated E3 ligase complex directly ubiquitylates CSB. The authors next wanted to assess the biological importance of CSB degradation post UV treatment. Building on an earlier observation that cellular exposure to a proteasome inhibitor suppresses RNA synthesis recovery [85], Groisman et al. determined that CSB persists in the CSA complex in MG132-treated cells and that the residual RNA synthesis recovery in CS-A or CS-B cells is insensitive to MG132 [28]. Thus, CSB degradation mediated by the CSA E3 ubiquitin ligase complex is necessary to remove CSB from the DNA after it has fulfilled its role to recruit NER proteins so that transcription can recover at the repaired site. In a more recent study, evidence was presented that BRCA1 poly-ubiquitylates CSB protein leading to CSB degradation and resulting in improved UV resistance, suggesting a pathway in addition to the CSA-dependent one [29].

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