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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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MlB1 ubiquitin ligase and NEK11 kinase influence BLM stability which has outcomes for non-homologous end-joining and suppression of sister chromatid exchange. Certain aspects of this model are debated. See text for details.
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biomolecules-05-00590-f005: MlB1 ubiquitin ligase and NEK11 kinase influence BLM stability which has outcomes for non-homologous end-joining and suppression of sister chromatid exchange. Certain aspects of this model are debated. See text for details.

Mentions: Given the apparent importance of BLM protein interactions for BLM stability, understanding the molecular mechanisms and cellular pathways involved is an active area of investigation. Wang et al. discovered a cell cycle-regulated interaction between BLM and TopBP1 mediated by the 5th BRCT phosphoprotein-binding domain (BRCT5) in TopBP1 [22] (Figure 5). Mutation of Ser-338 in the N-terminal region of BLM (which is phosphorylated specifically during S-phase) strongly disrupted the BLM/TopBP1 interaction. However, in contrast to the Wang et al. study [22], Blackford et al. determined that phosphorylation of Ser-304 of BLM mediates the interaction with TopBP1; furthermore, disruption of the TopBP1-BLM interaction did not destabilize BLM protein [50]. Studies by Wang et al. showed that the S-phase specific protein kinase NEK11 is responsible for BLM-Ser-338 phosphorylation, and that depletion of NEK11 kinase significantly reduced BLM protein level [22] (Figure 5). Consistent with this observation, TopBP1 depletion dramatically decreased cellular BLM protein levels, and in turn, resulted in elevated SCE. Ectopic expression of wild-type TopBP1, but not a TopBP1 mutant lacking BRCT5, restored normal BLM protein level and reduced SCE. Although Blackford et al. observed that neither a deficiency in TopBP1 nor perturbation of the TopBP1-BLM interaction affected stability of BLM protein, they did observe that the interaction between BLM and TopBP1 is important to maintain genomic stability [50]. In another study, TopBP1 was found to interact with FANCJ [44], which was aforementioned to affect BLM stability [42]. However, expression of a TopBP1 mutant protein lacking BRCT domains 7 and 8, which mediate the interaction with FANCJ [44], restored normal BLM protein level and SCE [22], indicating a FANCJ-independent effect of TopBP1 on BLM protein stability and its role in genome maintenance through suppression of cross-overs.


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)

MlB1 ubiquitin ligase and NEK11 kinase influence BLM stability which has outcomes for non-homologous end-joining and suppression of sister chromatid exchange. Certain aspects of this model are debated. See text for details.
© Copyright Policy
Related In: Results  -  Collection

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

biomolecules-05-00590-f005: MlB1 ubiquitin ligase and NEK11 kinase influence BLM stability which has outcomes for non-homologous end-joining and suppression of sister chromatid exchange. Certain aspects of this model are debated. See text for details.
Mentions: Given the apparent importance of BLM protein interactions for BLM stability, understanding the molecular mechanisms and cellular pathways involved is an active area of investigation. Wang et al. discovered a cell cycle-regulated interaction between BLM and TopBP1 mediated by the 5th BRCT phosphoprotein-binding domain (BRCT5) in TopBP1 [22] (Figure 5). Mutation of Ser-338 in the N-terminal region of BLM (which is phosphorylated specifically during S-phase) strongly disrupted the BLM/TopBP1 interaction. However, in contrast to the Wang et al. study [22], Blackford et al. determined that phosphorylation of Ser-304 of BLM mediates the interaction with TopBP1; furthermore, disruption of the TopBP1-BLM interaction did not destabilize BLM protein [50]. Studies by Wang et al. showed that the S-phase specific protein kinase NEK11 is responsible for BLM-Ser-338 phosphorylation, and that depletion of NEK11 kinase significantly reduced BLM protein level [22] (Figure 5). Consistent with this observation, TopBP1 depletion dramatically decreased cellular BLM protein levels, and in turn, resulted in elevated SCE. Ectopic expression of wild-type TopBP1, but not a TopBP1 mutant lacking BRCT5, restored normal BLM protein level and reduced SCE. Although Blackford et al. observed that neither a deficiency in TopBP1 nor perturbation of the TopBP1-BLM interaction affected stability of BLM protein, they did observe that the interaction between BLM and TopBP1 is important to maintain genomic stability [50]. In another study, TopBP1 was found to interact with FANCJ [44], which was aforementioned to affect BLM stability [42]. However, expression of a TopBP1 mutant protein lacking BRCT domains 7 and 8, which mediate the interaction with FANCJ [44], restored normal BLM protein level and SCE [22], indicating a FANCJ-independent effect of TopBP1 on BLM protein stability and its role in genome maintenance through suppression of cross-overs.

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