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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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HLTF degradation enables translesion polymerase bypass of alkylated DNA damage. See text for details.
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biomolecules-05-00590-f011: HLTF degradation enables translesion polymerase bypass of alkylated DNA damage. See text for details.

Mentions: Lin et al. performed studies with human cells to delineate the role of HLTF from another human Rad5-related protein known as SNF2 Histone-linker PHD-finger RING-finger Helicase (SHPRH) [82]. Loss of SHPRH or HLTF causes chromosomal instability after cellular exposure to DNA damaging agents; furthermore, both proteins poly-ubiquitylate the mono-ubiquitylated form of PCNA in a manner that is important for damage avoidance. In a clever series of experiments, the authors distinguished the mechanisms whereby HLTF and SHPRH operate in a damage-specific manner, i.e., HTLF suppresses UV light-induced mutagenesis and SHPRH suppresses methylmethanesulfonate (MMS)-induced mutagenesis. Cellular exposure to the alkylating agent MMS causes HLTF to be ubiquitylated and degraded in a proteasome-dependent manner, thereby promoting SHPRH to interact with Rad18 and polymerase kappa. Thus, the MMS-induced degradation of HLTF facilitates a pathway choice mediated by SHPRH because otherwise HLTF would compete with SHPRH for Rad18 binding (Figure 11). On the other hand, UV exposure causes HLTF to enhance PCNA mono-ubiquitylation, polymerase eta recruitment, and inhibition of SHPRH function. In either scenario, the recruitment of the most appropriate TLS polymerase to a specific replication blocking lesion enables an optimal bypass mechanism of PRR to minimize mutagenesis, presumably by ensuing fork progression thereby preventing fork stalling, fork collapse, and gross chromosomal rearrangements. The balancing act between HLTF and SHPRH is likely to play a paramount role in their tumor suppressor functions as they operate to suppress mutagenesis in a damage-specific manner.


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)

HLTF degradation enables translesion polymerase bypass of alkylated DNA damage. See text for details.
© Copyright Policy
Related In: Results  -  Collection

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

biomolecules-05-00590-f011: HLTF degradation enables translesion polymerase bypass of alkylated DNA damage. See text for details.
Mentions: Lin et al. performed studies with human cells to delineate the role of HLTF from another human Rad5-related protein known as SNF2 Histone-linker PHD-finger RING-finger Helicase (SHPRH) [82]. Loss of SHPRH or HLTF causes chromosomal instability after cellular exposure to DNA damaging agents; furthermore, both proteins poly-ubiquitylate the mono-ubiquitylated form of PCNA in a manner that is important for damage avoidance. In a clever series of experiments, the authors distinguished the mechanisms whereby HLTF and SHPRH operate in a damage-specific manner, i.e., HTLF suppresses UV light-induced mutagenesis and SHPRH suppresses methylmethanesulfonate (MMS)-induced mutagenesis. Cellular exposure to the alkylating agent MMS causes HLTF to be ubiquitylated and degraded in a proteasome-dependent manner, thereby promoting SHPRH to interact with Rad18 and polymerase kappa. Thus, the MMS-induced degradation of HLTF facilitates a pathway choice mediated by SHPRH because otherwise HLTF would compete with SHPRH for Rad18 binding (Figure 11). On the other hand, UV exposure causes HLTF to enhance PCNA mono-ubiquitylation, polymerase eta recruitment, and inhibition of SHPRH function. In either scenario, the recruitment of the most appropriate TLS polymerase to a specific replication blocking lesion enables an optimal bypass mechanism of PRR to minimize mutagenesis, presumably by ensuing fork progression thereby preventing fork stalling, fork collapse, and gross chromosomal rearrangements. The balancing act between HLTF and SHPRH is likely to play a paramount role in their tumor suppressor functions as they operate to suppress mutagenesis in a damage-specific manner.

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