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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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Proteolytic degradation of DNA helicases and helicase-like proteins. Protein interactions (A) and post-translational modifications (B) of DNA helicases or helicase-like proteins affect their stability. In a number of cases, protein interactions or post-translational modifications of helicase proteins affect their ubiquitylation which in turn influences stability via a proteasome degradation pathway. Post-translational modification of helicase proteins by ubiquitylating enzymes are listed in Table 1. See text for details. Blue, helicase or helicase-like protein; Maroon, helicase-interacting DNA repair and/or replication protein; Green, protein kinase; Yellow, acetyltransferase. The asterisk in Panel A indicates that BRCA1 has an intrinsic ubiquitin ligase activity. The asterisks in Panel B indicate the involvement of phosphorylation by protein kinases (NEK11, CHK1, PlK1) or acetylation by acetyltransferases (p300, CBP) in helicase protein stability.
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biomolecules-05-00590-f001: Proteolytic degradation of DNA helicases and helicase-like proteins. Protein interactions (A) and post-translational modifications (B) of DNA helicases or helicase-like proteins affect their stability. In a number of cases, protein interactions or post-translational modifications of helicase proteins affect their ubiquitylation which in turn influences stability via a proteasome degradation pathway. Post-translational modification of helicase proteins by ubiquitylating enzymes are listed in Table 1. See text for details. Blue, helicase or helicase-like protein; Maroon, helicase-interacting DNA repair and/or replication protein; Green, protein kinase; Yellow, acetyltransferase. The asterisk in Panel A indicates that BRCA1 has an intrinsic ubiquitin ligase activity. The asterisks in Panel B indicate the involvement of phosphorylation by protein kinases (NEK11, CHK1, PlK1) or acetylation by acetyltransferases (p300, CBP) in helicase protein stability.

Mentions: Yet another mechanism for modulation of helicase function is mediated by protein degradation pathways. In this scenario, the very stability of DNA helicase or helicase-like proteins is affected by cellular responses to stress that cause their proteolytic degradation. Regulation of proteins implicated in the DNA damage response or replication via their degradation is not unprecedented. For example, in yeast, proteasome degradation of replisome proteins regulates genomic stability [17]. However, much less is known about the intricacy of genome maintenance pathways and how they are regulated by proteasome degradation in higher eukaryotes. This review will provide a unique perspective on the topic of mammalian helicase protein degradation pathways to inform the reader of the emerging mechanisms that cells use to regulate helicase-dependent DNA repair, checkpoint signaling, and gene expression. Typically, helicase protein interactions play a major role in conferring helicase protein stability (Figure 1A), and the degradation of DNA helicases is frequently mediated by a ubiquitin-proteasome system in which the ubiquitin ligase complexes responsible for signaling proteasomal degradation have been identified (Table 1). In some cases, post-translational modifications such as phosphorylation or acetylation are involved (Figure 1B). We will discuss examples of helicase degradation pathways with a focus on human DNA helicases implicated in the cellular response to DNA damage or replication stress. Collectively, the evidence suggests that helicase degradation is an important regulatory mechanism which may be under-appreciated. Understanding helicase degradation pathways is likely to provide important insights to molecular-genetic diseases and potential avenues for therapy.


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)

Proteolytic degradation of DNA helicases and helicase-like proteins. Protein interactions (A) and post-translational modifications (B) of DNA helicases or helicase-like proteins affect their stability. In a number of cases, protein interactions or post-translational modifications of helicase proteins affect their ubiquitylation which in turn influences stability via a proteasome degradation pathway. Post-translational modification of helicase proteins by ubiquitylating enzymes are listed in Table 1. See text for details. Blue, helicase or helicase-like protein; Maroon, helicase-interacting DNA repair and/or replication protein; Green, protein kinase; Yellow, acetyltransferase. The asterisk in Panel A indicates that BRCA1 has an intrinsic ubiquitin ligase activity. The asterisks in Panel B indicate the involvement of phosphorylation by protein kinases (NEK11, CHK1, PlK1) or acetylation by acetyltransferases (p300, CBP) in helicase protein stability.
© Copyright Policy
Related In: Results  -  Collection

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

biomolecules-05-00590-f001: Proteolytic degradation of DNA helicases and helicase-like proteins. Protein interactions (A) and post-translational modifications (B) of DNA helicases or helicase-like proteins affect their stability. In a number of cases, protein interactions or post-translational modifications of helicase proteins affect their ubiquitylation which in turn influences stability via a proteasome degradation pathway. Post-translational modification of helicase proteins by ubiquitylating enzymes are listed in Table 1. See text for details. Blue, helicase or helicase-like protein; Maroon, helicase-interacting DNA repair and/or replication protein; Green, protein kinase; Yellow, acetyltransferase. The asterisk in Panel A indicates that BRCA1 has an intrinsic ubiquitin ligase activity. The asterisks in Panel B indicate the involvement of phosphorylation by protein kinases (NEK11, CHK1, PlK1) or acetylation by acetyltransferases (p300, CBP) in helicase protein stability.
Mentions: Yet another mechanism for modulation of helicase function is mediated by protein degradation pathways. In this scenario, the very stability of DNA helicase or helicase-like proteins is affected by cellular responses to stress that cause their proteolytic degradation. Regulation of proteins implicated in the DNA damage response or replication via their degradation is not unprecedented. For example, in yeast, proteasome degradation of replisome proteins regulates genomic stability [17]. However, much less is known about the intricacy of genome maintenance pathways and how they are regulated by proteasome degradation in higher eukaryotes. This review will provide a unique perspective on the topic of mammalian helicase protein degradation pathways to inform the reader of the emerging mechanisms that cells use to regulate helicase-dependent DNA repair, checkpoint signaling, and gene expression. Typically, helicase protein interactions play a major role in conferring helicase protein stability (Figure 1A), and the degradation of DNA helicases is frequently mediated by a ubiquitin-proteasome system in which the ubiquitin ligase complexes responsible for signaling proteasomal degradation have been identified (Table 1). In some cases, post-translational modifications such as phosphorylation or acetylation are involved (Figure 1B). We will discuss examples of helicase degradation pathways with a focus on human DNA helicases implicated in the cellular response to DNA damage or replication stress. Collectively, the evidence suggests that helicase degradation is an important regulatory mechanism which may be under-appreciated. Understanding helicase degradation pathways is likely to provide important insights to molecular-genetic diseases and potential avenues for therapy.

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