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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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Related in: MedlinePlus

Chk1 phosphorylation of BLM prevents its degradation by Cullin E3 ubiquitin ligase, enabling BLM to collaborate with PICH and resolve chromosomal bridges. See text for details.
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biomolecules-05-00590-f006: Chk1 phosphorylation of BLM prevents its degradation by Cullin E3 ubiquitin ligase, enabling BLM to collaborate with PICH and resolve chromosomal bridges. See text for details.

Mentions: In the latest work on how BLM function is regulated by its own degradation, post-translational modification by phosphorylation of a BLM residue that is different from that one targeted by NEK11 (mentioned above, [22]) was discovered. In this case, rather than modulating the protein interaction of BLM with TopBP1, the constitutive phosphorylation of BLM at Ser-502 by checkpoint kinase 1 (Chk1) enables BLM to localize to chromatin bridges where it is believed that the helicase inhibits HR or operates with another helicase known as Polo-like kinase 1-interacting checkpoint helicase (PICH) to unravel chromatin and promote resolution of incompletely segregated chromosomal DNA (i.e., bridges) that can form during anaphase [23] (Figure 6). Petsalaki et al. performed an elegant set of experiments characterizing BLM site-directed mutants in which Ser-502 was substituted with a non-phosphorylatable alanine (A) or phosphor-mimicking aspartic acid (D). The BLM-S502A mutation reduced BLM stability whereas the BLM-S502D mutation stabilized BLM allowing it to prevent chromatin bridges in Chk1-deficient cells. BLM degradation is mediated by the Cullin E3 ubiquitin ligase complex based on the observation that the two human recombinant proteins expressed in Chinese hamster ovary cells can be pulled down together and that depletion of Cullin inhibited BLM degradation and suppressed the accumulation of anaphase bridges in cells treated with a Chk1 inhibitor. Thus Chk1 phosphorylation of BLM Ser-502 blocks Cullin binding to BLM and prevents its degradation (Figure 6). It has not yet been determined if Chk1 phosphorylation of BLM at residue Ser-502 may affect other functions of BLM besides protection against chromatin bridges through its effect on BLM protein stabilization.


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)

Chk1 phosphorylation of BLM prevents its degradation by Cullin E3 ubiquitin ligase, enabling BLM to collaborate with PICH and resolve chromosomal bridges. See text for details.
© Copyright Policy
Related In: Results  -  Collection

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

biomolecules-05-00590-f006: Chk1 phosphorylation of BLM prevents its degradation by Cullin E3 ubiquitin ligase, enabling BLM to collaborate with PICH and resolve chromosomal bridges. See text for details.
Mentions: In the latest work on how BLM function is regulated by its own degradation, post-translational modification by phosphorylation of a BLM residue that is different from that one targeted by NEK11 (mentioned above, [22]) was discovered. In this case, rather than modulating the protein interaction of BLM with TopBP1, the constitutive phosphorylation of BLM at Ser-502 by checkpoint kinase 1 (Chk1) enables BLM to localize to chromatin bridges where it is believed that the helicase inhibits HR or operates with another helicase known as Polo-like kinase 1-interacting checkpoint helicase (PICH) to unravel chromatin and promote resolution of incompletely segregated chromosomal DNA (i.e., bridges) that can form during anaphase [23] (Figure 6). Petsalaki et al. performed an elegant set of experiments characterizing BLM site-directed mutants in which Ser-502 was substituted with a non-phosphorylatable alanine (A) or phosphor-mimicking aspartic acid (D). The BLM-S502A mutation reduced BLM stability whereas the BLM-S502D mutation stabilized BLM allowing it to prevent chromatin bridges in Chk1-deficient cells. BLM degradation is mediated by the Cullin E3 ubiquitin ligase complex based on the observation that the two human recombinant proteins expressed in Chinese hamster ovary cells can be pulled down together and that depletion of Cullin inhibited BLM degradation and suppressed the accumulation of anaphase bridges in cells treated with a Chk1 inhibitor. Thus Chk1 phosphorylation of BLM Ser-502 blocks Cullin binding to BLM and prevents its degradation (Figure 6). It has not yet been determined if Chk1 phosphorylation of BLM at residue Ser-502 may affect other functions of BLM besides protection against chromatin bridges through its effect on BLM protein stabilization.

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