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.
Highlights
IntroductionDNA helicases are a class of enzymes that unwind structured deoxyribonucleic acids in an ATP-dependent manner by translocating in a directionally specific manner (5' to 3' or 3' to 5' with respect to the strand the helicase is predominantly bound), and play essential roles in genome integrity [1,2,3,4,5,6,7]
DNA helicases are a class of enzymes that unwind structured deoxyribonucleic acids in an ATP-dependent manner by translocating in a directionally specific manner (5' to 3' or 3' to 5' with respect to the strand the helicase is predominantly bound), and play essential roles in genome integrity [1,2,3,4,5,6,7].DNA helicases are classified according to their amino acid conservation within the helicase core domain that is implicated in DNA binding and nucleoside triphosphate hydrolysis
Luke-Glasser et al found that FANCM is necessary for resumption of DNA synthesis after a replication block induced by the topoisomerase inhibitor camptothecin (CPT) [57]
Summary
DNA helicases are a class of enzymes that unwind structured deoxyribonucleic acids in an ATP-dependent manner by translocating in a directionally specific manner (5' to 3' or 3' to 5' with respect to the strand the helicase is predominantly bound), and play essential roles in genome integrity [1,2,3,4,5,6,7]. The tumor suppressor p53 can inhibit unwinding or branch-migration catalyzed by certain DNA helicases like BLM and WRN defective in Bloom’s syndrome and Werner syndrome, respectively [13,14] Another mechanism of helicase modulation occurs through post-translational covalent modifications of helicase proteins including phosphorylation, acetylation, SUMOylation, and ubiquitylation (for review, see [15,16]). 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. 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. Understanding helicase degradation pathways is likely to provide important insights to molecular-genetic diseases and potential avenues for therapy
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