Single-strand break repair and genetic disease
TL;DR: The molecular mechanisms and organization of the DNA-repair pathways that remove single-strand breaks are reviewed and the connection between defects in these pathways and hereditary neurodegenerative disease are discussed.
Abstract: Hereditary defects in the repair of DNA damage are implicated in a variety of diseases, many of which are typified by neurological dysfunction and/or increased genetic instability and cancer. Of the different types of DNA damage that arise in cells, single-strand breaks (SSBs) are the most common, arising at a frequency of tens of thousands per cell per day from direct attack by intracellular metabolites and from spontaneous DNA decay. Here, the molecular mechanisms and organization of the DNA-repair pathways that remove SSBs are reviewed and the connection between defects in these pathways and hereditary neurodegenerative disease are discussed.
Citations
More filters
TL;DR: The authors' improving understanding of DNA-damage responses is providing new avenues for disease management, and these responses are biologically significant because they prevent diverse human diseases.
Abstract: The prime objective for every life form is to deliver its genetic material, intact and unchanged, to the next generation. This must be achieved despite constant assaults by endogenous and environmental agents on the DNA. To counter this threat, life has evolved several systems to detect DNA damage, signal its presence and mediate its repair. Such responses, which have an impact on a wide range of cellular events, are biologically significant because they prevent diverse human diseases. Our improving understanding of DNA-damage responses is providing new avenues for disease management.
4,871 citations
TL;DR: This review will focus on how the DDR controls DNA repair and the phenotypic consequences of defects in these critical regulatory functions in mammals.
3,678 citations
Cites background from "Single-strand break repair and gene..."
...SSBs are repaired by single-strand break repair (SSBR), whereas DSBs are processed either by nonhomologous end joining (NHEJ) or homologous recombination (HR) (Caldecott, 2008; West, 2003)....
[...]
...Several DDR factors contain the acid basic residue-rich cluster, including p53, XRCC1, LIG3, MRE11, and ATM, whereas PBZ motifs have recently been identified in the nucleases APLF and SNM1 and in the cell-cycle checkpoint protein CHFR (Ahel et al., 2008; Gagné et al., 2008)....
[...]
...The neurodegenerative disorders ataxia with axonal neuropathy (SCAN1) and ataxia with oculomotor apraxia 1 (AOA1) are caused by mutations of the DNA end-processing enzymes TDP1 and APTX, respectively (Caldecott, 2008)....
[...]
...APLF is dependent on the PBZ motif for its recruitment to DNA damage sites (Bekker-Jensen et al., 2007; Kanno et al., 2007; Rulten et al., 2008)....
[...]
...DNA termini that contain nonligatable end groups are processed by the ARTEMIS and APLF nucleases and the PNK kinase/phosphatase prior to DNA ligation (Mahaney et al., 2009)....
[...]
TL;DR: Genetic evidence suggests that tumour cells may also require specific interphase CDKs for proliferation, and selective CDK inhibition may provide therapeutic benefit against certain human neoplasias.
Abstract: Tumour-associated cell cycle defects are often mediated by alterations in cyclin-dependent kinase (CDK) activity. Misregulated CDKs induce unscheduled proliferation as well as genomic and chromosomal instability. According to current models, mammalian CDKs are essential for driving each cell cycle phase, so therapeutic strategies that block CDK activity are unlikely to selectively target tumour cells. However, recent genetic evidence has revealed that, whereas CDK1 is required for the cell cycle, interphase CDKs are only essential for proliferation of specialized cells. Emerging evidence suggests that tumour cells may also require specific interphase CDKs for proliferation. Thus, selective CDK inhibition may provide therapeutic benefit against certain human neoplasias.
3,146 citations
TL;DR: Evidence that cancer and diseases of aging are two sides of the DNAdamage problem is presented, followed by an account of the derailment of genome guardian mechanisms in cancer and of how this cancerspecific phenomenon can be exploited for treatment.
Abstract: NA damage has emerged as a major culprit in cancer and many diseases related to aging. The stability of the genome is supported by an intricate machinery of repair, damage tolerance, and checkpoint pathways that counteracts DNA damage. In addition, DNA damage and other stresses can trigger a highly conserved, anticancer, antiaging survival response that suppresses metabolism and growth and boosts defenses that maintain the integrity of the cell. Induction of the survival response may allow interventions that improve health and extend the life span. Recently, the first candidate for such interventions, rapamycin (also known as sirolimus), has been identified. 1 Compromised repair systems in tumors also offer opportunities for intervention, making it possible to attack malignant cells in which maintenance of the genome has been weakened. Time-dependent accumulation of damage in cells and organs is associated with gradual functional decline and aging. 2 The molecular basis of this phenomenon is unclear, 3-5 whereas in cancer, DNA alterations are the major culprit. In this review, I present evidence that cancer and diseases of aging are two sides of the DNAdamage problem. An examination of the importance of DNA damage and the systems of genome maintenance in relation to aging is followed by an account of the derailment of genome guardian mechanisms in cancer and of how this cancerspecific phenomenon can be exploited for treatment.
1,917 citations
TL;DR: How the development of various complementary methodologies has provided valuable insights into the spatiotemporal dynamics of DDR protein assembly/disassembly at sites of DNA strand breaks in eukaryotic cells is outlined.
Abstract: Genome integrity is constantly monitored by sophisticated cellular networks, collectively termed the DNA damage response (DDR). A common feature of DDR proteins is their mobilization in response to genotoxic stress. Here, we outline how the development of various complementary methodologies has provided valuable insights into the spatiotemporal dynamics of DDR protein assembly/disassembly at sites of DNA strand breaks in eukaryotic cells. Considerable advances have also been made in understanding the underlying molecular mechanisms for these events, with post-translational modifications of DDR factors being shown to play prominent roles in controlling the formation of foci in response to DNA-damaging agents. We review these regulatory mechanisms and discuss their biological significance to the DDR.
1,051 citations
Cites background from "Single-strand break repair and gene..."
...Although not as harmful as DSBs, SSBs are toxic to the cell, as they can block DNA replication and transcription, and, indeed, SSBR defects are associated with several hereditary neurodegenerative diseases (Caldecott 2008)....
[...]
References
More filters
TL;DR: In this review, the cellular roles of these enzymes are examined from a molecular point of view.
Abstract: DNA topoisomerases are the magicians of the DNA world — by allowing DNA strands or double helices to pass through each other, they can solve all of the topological problems of DNA in replication, transcription and other cellular transactions. Extensive biochemical and structural studies over the past three decades have provided molecular models of how the various subfamilies of DNA topoisomerase manipulate DNA. In this review, the cellular roles of these enzymes are examined from a molecular point of view.
2,194 citations
"Single-strand break repair and gene..." refers background in this paper
...TOP1 creates a 'cleavage complex' intermediate containing a DNA nick in order to relax DNA during transcription and DNA replicatio...
[...]
TL;DR: The total dependence of poly(ADP-ribose) synthesis on DNA strand breaks strongly suggests that this post-translational modification is involved in the metabolism of nucleic acids, and the presence of PARP in these multiprotein complexes clearly supports an important role for poly(ADE-ribosyl)ation reactions in DNA transactions.
Abstract: Poly(ADP-ribosyl)ation is a post-translational modification of proteins. During this process, molecules of ADP-ribose are added successively on to acceptor proteins to form branched polymers. This modification is transient but very extensive in vivo, as polymer chains can reach more than 200 units on protein acceptors. The existence of the poly(ADP-ribose) polymer was first reported nearly 40 years ago. Since then, the importance of poly(ADP-ribose) synthesis has been established in many cellular processes. However, a clear and unified picture of the physiological role of poly(ADP-ribosyl)ation still remains to be established. The total dependence of poly(ADP-ribose) synthesis on DNA strand breaks strongly suggests that this post-translational modification is involved in the metabolism of nucleic acids. This view is also supported by the identification of direct protein-protein interactions involving poly(ADP-ribose) polymerase (113 kDa PARP), an enzyme catalysing the formation of poly(ADP-ribose), and key effectors of DNA repair, replication and transcription reactions. The presence of PARP in these multiprotein complexes, in addition to the actual poly(ADP-ribosyl)ation of some components of these complexes, clearly supports an important role for poly(ADP-ribosyl)ation reactions in DNA transactions. Accordingly, inhibition of poly(ADP-ribose) synthesis by any of several approaches and the analysis of PARP-deficient cells has revealed that the absence of poly(ADP-ribosyl)ation strongly affects DNA metabolism, most notably DNA repair. The recent identification of new poly(ADP-ribosyl)ating enzymes with distinct (non-standard) structures in eukaryotes and archaea has revealed a novel level of complexity in the regulation of poly(ADP-ribose) metabolism.
1,797 citations
"Single-strand break repair and gene..." refers background in this paper
...SBs arising directly from disintegration of oxidized deoxyribose are primarily detected by PARP1, although contributions from other members of the PARP superfamily are possibl...
[...]
TL;DR: This review summarizes the present knowledge of this emerging superfamily of Poly(ADP‐ribose) polymerases, which might ultimately improve pharmacological strategies to enhance both antitumor efficacy and the treatment of a number of inflammatory and neurodegenerative disorders.
Abstract: Poly(ADP-ribosyl)ation is an immediate DNA-damage-dependent post-translational modification of histones and other nuclear proteins that contributes to the survival of injured proliferating cells. Poly(ADP-ribose) polymerases (PARPs) now constitute a large family of 18 proteins, encoded by different genes and displaying a conserved catalytic domain in which PARP-1 (113 kDa), the founding member, and PARP-2 (62 kDa) are so far the sole enzymes whose catalytic activity has been shown to be immediately stimulated by DNA strand breaks. A large repertoire of sequences encoding novel PARPs now extends considerably the field of poly(ADP-ribosyl)ation reactions to various aspects of the cell biology including cell proliferation and cell death. Some of these new members interact with each other, share common partners and common subcellular localizations suggesting possible fine tuning in the regulation of this post-translational modification of proteins. This review summarizes our present knowledge of this emerging superfamily, which might ultimately improve pharmacological strategies to enhance both antitumor efficacy and the treatment of a number of inflammatory and neurodegenerative disorders. A provisional nomenclature is proposed.
1,355 citations
"Single-strand break repair and gene..." refers background in this paper
...SBs arising directly from disintegration of oxidized deoxyribose are primarily detected by PARP1, although contributions from other members of the PARP superfamily are possibl...
[...]
TL;DR: It is demonstrated that one function of (ADP–ribose)n is to participate in the cellular recovery from DNA damage, and specific inhibitors of poly(ADP-ribose] polymerase prevent rejoining of DNA strand breaks caused by dimethyl sulphate and cytotoxicity is enhanced thereby.
Abstract: Chromatin proteins are covalently modified by at least five different processes; in no case has the precise physiological function been established. One of these post-synthetic, covalent modifications is effected by the enzyme poly(ADP-ribose) polymerase, which uses the coenzyme NAD+ to ADP-ribosylate chromatin proteins. The modification consists largely of mono(ADP-ribose), but long, homopolymer chains of (ADP-ribose) are also present. Various physiological functions have been suggested for (ADP-ribose)n. Here we demonstrate that one function of (ADP-ribose)n is to participate in the cellular recovery from DNA damage. Specific inhibitors of poly(ADP-ribose) polymerase prevent rejoining of DNA strand breaks caused by dimethyl sulphate and cytotoxicity is enhanced thereby. The rejoining of strand breaks is prevented also by nutritionally depleting the cells of NAD.
1,081 citations
"Single-strand break repair and gene..." refers background in this paper
...PARP1 is also activated at SSBs that arise indirectly during BE...
[...]
TL;DR: This work has shown the ability to characterize the sugar moiety through the mechanism of “sugar-by-sugar interactions” and has suggested a number of mechanisms that could be responsible for the sweetness of the sucrose molecule.
Abstract: ion from the Sugar Moiety Wendy Knapp Pogozelski† and Thomas D. Tullius*,‡ Department of Chemistry, State University of New York at Geneseo, Geneseo, New York 14454, and Department of Chemistry, Boston University, Boston, Massachusetts 02215 Received August 27, 1997 (Revised Manuscript Received February 26, 1998)
969 citations