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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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FANCM phosphorylation controls FANCM stability and its role at stalled replication forks. See text for details.
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biomolecules-05-00590-f008: FANCM phosphorylation controls FANCM stability and its role at stalled replication forks. See text for details.

Mentions: Although not a classic DNA helicase per se, FANCM is an ATP-dependent translocase capable of remodeling DNA structures associated with stalled replication forks [55]. FANCM is implicated in the FA pathway of ICL repair, and is more generally involved in the replication stress response. FANCM recruits the FA core complex to chromatin during S phase or the DNA damage response, and as mentioned above acts as a bridging molecule with the BLM protein to maintain chromosomal stability through BLM-TopoIIIα double Holliday Junction dissolution [56]. Work from the D’Andrea laboratory showed that FANCM is hyper-phosphorylated and proteolytically degraded during mitosis [25] (Figure 8). They found that the β-TRCP component of the SCF E3 ubiquitin ligase complex was responsible for FANCM proteolysis mediated by the presence in FANCM of a consensus DSGxxS consensus sequence that is implicated in SCFβ−TRCP degradation. The Plk1 kinase which regulates mitotic progression through its checkpoint functions is responsible for FANCM phosphorylation by recognition of a Polo-box domain, which serves to trigger subsequent FANCM degradation. Remarkably, FANCM degradation was shown to facilitate the release of the FA core complex from chromatin during mitosis (independent of its role in S-phase checkpoint), and this is required for the suppression of chromosomal radial formation induced by cellular exposure to the cross-linking agent MMC.


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)

FANCM phosphorylation controls FANCM stability and its role at stalled replication forks. See text for details.
© Copyright Policy
Related In: Results  -  Collection

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

biomolecules-05-00590-f008: FANCM phosphorylation controls FANCM stability and its role at stalled replication forks. See text for details.
Mentions: Although not a classic DNA helicase per se, FANCM is an ATP-dependent translocase capable of remodeling DNA structures associated with stalled replication forks [55]. FANCM is implicated in the FA pathway of ICL repair, and is more generally involved in the replication stress response. FANCM recruits the FA core complex to chromatin during S phase or the DNA damage response, and as mentioned above acts as a bridging molecule with the BLM protein to maintain chromosomal stability through BLM-TopoIIIα double Holliday Junction dissolution [56]. Work from the D’Andrea laboratory showed that FANCM is hyper-phosphorylated and proteolytically degraded during mitosis [25] (Figure 8). They found that the β-TRCP component of the SCF E3 ubiquitin ligase complex was responsible for FANCM proteolysis mediated by the presence in FANCM of a consensus DSGxxS consensus sequence that is implicated in SCFβ−TRCP degradation. The Plk1 kinase which regulates mitotic progression through its checkpoint functions is responsible for FANCM phosphorylation by recognition of a Polo-box domain, which serves to trigger subsequent FANCM degradation. Remarkably, FANCM degradation was shown to facilitate the release of the FA core complex from chromatin during mitosis (independent of its role in S-phase checkpoint), and this is required for the suppression of chromosomal radial formation induced by cellular exposure to the cross-linking agent MMC.

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