Limits...
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.

Show MeSH

Related in: MedlinePlus

FBH1 proteolysis is governed by its interaction with PCNA during the UV-induced DNA damage response. See text for details.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4496686&req=5

biomolecules-05-00590-f009: FBH1 proteolysis is governed by its interaction with PCNA during the UV-induced DNA damage response. See text for details.

Mentions: Controlling repair of DSBs by modulating the functions of DNA helicases is a theme that is highly prevalent for maintenance of genomic stability [2]. The human F-box DNA helicase (FBH1) is known to regulate HR that might occur at stalled replication forks [60,61]. Bacquin et al. found that while PCNA serves to recruit FBH1 to sites of DNA replication and DNA damage via a direct physical interaction and facilitates its anti-recombinase activity, degradation of FBH1 is enhanced after ultraviolet (UV) light irradiation via the E3 ubiquitin ligase Cullin-ring ligase 4-Cdt2 (CRL4Cdt2) in a manner that is dependent on FBH1’s interaction with PCNA [26] (Figure 9). The authors proceeded to show that expression of a non-degradable FBH1 mutant diminished recruitment of the translesion polymerase Pol η to chromatin in UV-irradiated cells. This leads to the scenario in which FBH1 degradation via CRL4Cdt2-PCNA is necessary so that FBH1 can be removed from the site of the replication-blocking lesion so that the TLS polymerase can gain access and perform bypass DNA synthesis. Although it may seem antithetical, the degradation of FBH1 is necessary to insure PCNA-dependent balance of HR and TLS in human cells.


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)

FBH1 proteolysis is governed by its interaction with PCNA during the UV-induced DNA damage response. See text for details.
© Copyright Policy
Related In: Results  -  Collection

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

biomolecules-05-00590-f009: FBH1 proteolysis is governed by its interaction with PCNA during the UV-induced DNA damage response. See text for details.
Mentions: Controlling repair of DSBs by modulating the functions of DNA helicases is a theme that is highly prevalent for maintenance of genomic stability [2]. The human F-box DNA helicase (FBH1) is known to regulate HR that might occur at stalled replication forks [60,61]. Bacquin et al. found that while PCNA serves to recruit FBH1 to sites of DNA replication and DNA damage via a direct physical interaction and facilitates its anti-recombinase activity, degradation of FBH1 is enhanced after ultraviolet (UV) light irradiation via the E3 ubiquitin ligase Cullin-ring ligase 4-Cdt2 (CRL4Cdt2) in a manner that is dependent on FBH1’s interaction with PCNA [26] (Figure 9). The authors proceeded to show that expression of a non-degradable FBH1 mutant diminished recruitment of the translesion polymerase Pol η to chromatin in UV-irradiated cells. This leads to the scenario in which FBH1 degradation via CRL4Cdt2-PCNA is necessary so that FBH1 can be removed from the site of the replication-blocking lesion so that the TLS polymerase can gain access and perform bypass DNA synthesis. Although it may seem antithetical, the degradation of FBH1 is necessary to insure PCNA-dependent balance of HR and TLS in human cells.

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