Source: https://chemweb.com/articles/SV10541/0007600001
Timestamp: 2019-04-22 02:07:54+00:00

Document:
Chronicle of recent events by V. P. Skulachev; R. D. Ozrina (1-2).
DNA repair: a key mechanism stabilizing the genome by O. I. Lavrik (3-3).
Role of nucleotide excision repair proteins in oxidative DNA damage repair: an updating by B. Pascucci; M. D’Errico; E. Parlanti; S. Giovannini; E. Dogliotti (4-15).
DNA repair is a crucial factor in maintaining a low steady-state level of oxidative DNA damage. Base excision repair (BER) has an important role in preventing the deleterious effects of oxidative DNA damage, but recent evidence points to the involvement of several repair pathways in this process. Oxidative damage may arise from endogenous and exogenous sources and may target nuclear and mitochondrial DNA as well as RNA and proteins. The importance of preventing mutations associated with oxidative damage is shown by a direct association between defects in BER (i.e. MYH DNA glycosylase) and colorectal cancer, but it is becoming increasingly evident that damage by highly reactive oxygen species plays also central roles in aging and neurodegeneration. Mutations in genes of the nucleotide excision repair (NER) pathway are associated with diseases, such as xeroderma pigmentosum and Cockayne syndrome, that involve increased skin cancer risk and/or developmental and neurological symptoms. In this review we will provide an updating of the current evidence on the involvement of NER factors in the control of oxidative DNA damage and will attempt to address the issue of whether this unexpected role may unlock the difficult puzzle of the pathogenesis of these syndromes.
Multiple DNA damage recognition factors involved in mammalian nucleotide excision repair by K. Sugasawa (16-23).
The nucleotide excision repair (NER) subpathway operating throughout the mammalian genome is a versatile DNA repair system that can remove a wide variety of helix-distorting base lesions. This system contributes to prevention of blockage of DNA replication by the lesions, thereby suppressing mutagenesis and carcinogenesis. Therefore, it is of fundamental significance to understand how the huge genome can be surveyed for occurrence of a small number of lesions. Recent studies have revealed that this difficult task seems to be accomplished through sequential actions of multiple DNA damage recognition factors, including UV-DDB, XPC, and TFIIH. Notably, these factors adopt completely different strategies to recognize DNA damage. XPC detects disruption and/or destabilization of the base pairing, which ensures a broad spectrum of substrate specificity for global genome NER. In contrast, UV-DDB directly recognizes particular types of lesions, such as UV-induced photoproducts, thereby vitally recruiting XPC as well as further extending the substrate specificity. After DNA binding by XPC, moreover, the helicase activity associated with TFIIH scans a DNA strand to make a final search for the presence of aberrant chemical modifications of DNA. The combination of these different strategies makes a crucial contribution to simultaneously achieving efficiency, accuracy, and versatility of the entire repair system.
Nucleotide excision repair: DNA damage recognition and preincision complex assembly by N. I. Rechkunova; Yu. S. Krasikova; O. I. Lavrik (24-35).
Nucleotide excision repair (NER) is one of the major DNA repair pathways in eukaryotic cells counteracting genetic changes caused by DNA damage. NER removes a wide set of structurally diverse lesions such as pyrimidine dimers arising upon UV irradiation and bulky chemical adducts arising upon exposure to carcinogens or chemotherapeutic drugs. NER defects lead to severe diseases including some forms of cancer. In view of the broad substrate specificity of NER, it is of interest to understand how a certain set of proteins recognizes various DNA lesions in the context of a large excess of intact DNA. This review focuses on DNA damage recognition and following stages resulting in preincision complex assembly, the key and still most unclear steps of NER. The major models of primary damage recognition and preincision complex assembly are considered. The contribution of affinity labeling techniques in study of this process is discussed.
Fanconi anemia: at the Crossroads of DNA repair by J. S. Deakyne; A. V. Mazin (36-48).
Fanconi anemia (FA) is an autosomal disorder that causes genome instability. FA patients suffer developmental abnormalities, early-onset bone marrow failure, and a predisposition to cancer. The disease is manifested by defects in DNA repair, hypersensitivity to DNA crosslinking agents, and a high degree of chromosomal aberrations. The FA pathway comprises 13 disease-causing genes involved in maintaining genomic stability. The fast pace of study of the novel DNA damage network has led to the constant discovery of new FA-like genes involved in the pathway that when mutated lead to similar disorders. A majority of the FA proteins act as signal transducers and scaffolding proteins to employ other pathways to repair DNA. This review discusses what is known about the FA proteins and other recently linked FA-like proteins. The goal is to clarify how the proteins work together to carry out interstrand crosslink repair and homologous recombination-mediated repair of damaged DNA.
Participation of translesion synthesis DNA polymerases in the maintenance of chromosome integrity in yeast Saccharomyces cerevisiae by O. V. Kochenova; J. V. Soshkina; E. I. Stepchenkova; S. G. Inge-Vechtomov; P. V. Shcherbakova (49-60).
We employed a genetic assay based on illegitimate hybridization of heterothallic Saccharomyces cerevisiae strains (the α-test) to analyze the consequences for genome stability of inactivating translesion synthesis (TLS) DNA polymerases. The α-test is the only assay that measures the frequency of different types of mutational changes (point mutations, recombination, chromosome or chromosome arm loss) and temporary changes in genetic material simultaneously. All these events are manifested as illegitimate hybridization and can be distinguished by genetic analysis of the hybrids and cytoductants. We studied the effect of Polζ, Polη, and Rev1 deficiency on the genome stability in the absence of genotoxic treatment and in UV-irradiated cells. We show that, in spite of the increased percent of accurately repaired primary lesions, chromosome fragility, rearrangements, and loss occur in the absence of Polζ and Polη Our findings contribute to further refinement of the current models of translesion synthesis and the organization of eukaryotic replication fork.
DNA polymerase ι of mammals as a participant in translesion synthesis of DNA by L. V. Gening (61-68).
This review describes the properties of some specialized DNA polymerases participating in translesion synthesis of DNA. Special attention is given to these properties in vivo. DNA polymerase iota (Polι) of mammals has very unusual features and is extremely error-prone. Based on available data, a hypothesis is proposed explaining how mammalian cells can explore the unusual features of DNA Polι to bypass DNA damages and to simultaneously prevent its mutagenic potential.
Regulation of DNA repair by ubiquitylation by G. L. Dianov; C. Meisenberg; J. L. Parsons (69-79).
Cellular DNA repair is a frontline system that is responsible for maintaining genome integrity and thus preventing premature aging and cancer by repairing DNA lesions and strand breaks caused by endogenous and exogenous mutagens. However, it is also the principal cellular system in cancer cells that counteracts the killing effect of the major cancer treatments, e.g. chemotherapy and ionizing radiation. Although it is clear that an individual’s DNA repair capacity varies, the mechanisms involved in the regulation of repair systems that are responsible for such variations are only just emerging. This knowledge gap is impeding the finding of new cancer therapy targets and the development of novel treatment strategies. In recent years the vital role of post-translational modifications of DNA repair proteins, including ubiquitylation and phosphorylation, has been uncovered. This review will cover recent progress in our understanding of the role of ubiquitylation in the regulation of DNA repair.
Eukaryotic endonuclease VIII-Like proteins: New components of the base excision DNA repair system by I. R. Grin; D. O. Zharkov (80-93).
Base excision DNA repair is necessary for removal of damaged nucleobases from the genome and their replacement with normal nucleobases. Base excision repair is initiated by DNA glycosylases, the enzymes that cleave the N-glycosidic bonds of damaged deoxynucleotides. Until recently, only eight DNA glycosylases with different substrate specificity were known in human cells. In 2002, three new human DNA glycosylases (NEIL1, NEIL2, and NEIL3) were discovered, all homologous to endonuclease VIII, a bacterial protein, which also participates in DNA repair. The role of these enzymes remains mostly unknown. In this review we discuss recent data on the substrate specificity of the NEIL enzymes, their catalytic mechanism, structure, interactions with other components of DNA repair system, and possible biological role in preventing diseases associated with DNA damage.
Main factors providing specificity of repair enzymes by G. A. Nevinsky (94-117).
Specific and nonspecific DNA complex formation with human uracil-DNA glycosylase, 8-oxoguanine-DNA glycosylase, and apurine/apyrimidine endonuclease, as well as with E. coli 8-oxoguanine-DNA glycosylase and RecA protein was analyzed using the method of stepwise increase in DNA-ligand complexity. It is shown that high affinity of these enzymes to any DNA (10−4–10−8 M) is provided by a large number of weak additive contacts mainly with DNA internucleoside phosphate groups and in a less degree with bases of nucleotide links “covered” by protein globules. Enzyme interactions with specific DNA links are comparable in efficiency with weak unspecific contacts and provide only for one-two orders of affinity (10−1–10−2 M), but these contacts are extremely important at stages of DNA and enzyme structural adaptation and catalysis proper. Only in the case of specific DNA individual for each enzyme alterations in DNA structure provide for efficient adjustment of reacting enzyme atoms and DNA orbitals with accuracy up to 10–15° and, as a result, for high reaction rate. Upon transition from nonspecific to specific DNA, reaction rate (k cat) increases by 4–8 orders of magnitude. Thus, stages of DNA and enzyme structural adaptation as well as catalysis proper are the basis of specificity of repair enzymes.
Mechanism of recognition and repair of damaged DNA by human 8-oxoguanine DNA glycosylase hOGG1 by N. A. Kuznetsov; V. V. Koval; O. S. Fedorova (118-130).
Recent data on structural and biochemical features of human 8-oxoguanine DNA glycosylase (hOGG1) has enabled detailed evaluation of the mechanism by which the damaged DNA bases are recognized and eliminated from the chain. Pre-steady-state kinetic studies with recording of conformational transitions of the enzyme and DNA substrate significantly contribute to understanding of this mechanism. In this review we particularly focus on the interrelationship between the conformational changes of interacting molecules and kinetics of their interaction and on the nature of each elementary step during the enzymatic process. Exhaustive analysis of these data and detailed mechanism of hOGG1-catalyzed reaction are proposed.
Mutator effects and mutation signatures of editing deaminases produced in bacteria and yeast by A. G. Lada; C. Frahm Krick; S. G. Kozmin; V. I. Mayorov; T. S. Karpova; I. B. Rogozin; Y. I. Pavlov (131-146).
Enzymatic deamination of bases in DNA or RNA leads to an alteration of flow of genetic information. Adenosine deaminases edit RNA (ADARs, TADs). Specialized cytidine deaminases are involved in RNA/DNA editing in lipid metabolism (APOBEC1) and in innate (APOBEC3 family) and humoral (AID) immunity. APOBEC2 is required for proper muscle development and, along with AID, was implicated in demethylation of DNA. The functions of APOBEC4, APOBEC5, and other deaminases recently discovered by bioinformatics approaches are unknown. What is the basis for the diverse biological functions of enzymes with similar enzyme structure and the same principal enzymatic reaction? AID, APOBEC1, lamprey CDA1, and APOBEC3G enzymes cause uracil DNA glycosylase-dependent induction of mutations when overproduced ectopically in bacteria or yeast. APOBEC2, on the contrary, is nonmutagenic. We studied the effects of the expression of various deaminases in yeast and bacteria. The mutagenic specificities of four deaminases, hAID, rAPOBEC1, hAPOBEC3G, and lamprey CDA1, are strikingly different. This suggests the existence of an intrinsic component of deaminase targeting. The expression of yeast CDD1 and TAD2/TAD3, human APOBEC4, Xanthomonas oryzae APOBEC5, and deaminase encoded by Micromonas sp. gene MICPUN_56782 was nonmutagenic. A lack of a mutagenic effect for Cdd1 is expected because the enzyme functions in the salvage of pyrimidine nucleotides, and it is evolutionarily distant from RNA/DNA editing enzymes. The reason for inactivity of deaminases grouped with APOBEC2 is not obvious from their structures. This cannot be explained by protein insolubility and peculiarities of cellular distribution and requires further investigation.
Interaction of poly(ADP-ribose) polymerase 1 with apurinic/apyrimidinic sites within clustered DNA damage by M. M. Kutuzov; E. S. Ilina; M. V. Sukhanova; I. A. Pyshnaya; D. V. Pyshnyi; O. I. Lavrik; S. N. Khodyreva (147-156).
To study the interaction of poly(ADP-ribose) polymerase 1 (PARP1) with apurinic/apyrimidinic sites (AP sites) within clustered damages, DNA duplexes were created that contained an AP site in one strand and one of its analogs situated opposite the AP site in the complementary strand. Residues of 3-hydroxy-2-hydroxymethyltetrahydrofuran (THF), diethylene glycol (DEG), and decane-1,10-diol (DD) were used. It is shown for the first time that apurinic/apyrimidinic endonuclease 1 (APE1) cleaves the DNA strands at the positions of DEG and DD residues, and this suggests these groups as AP site analogs. Insertion of DEG and DD residues opposite an AP site decreased the rate of AP site hydrolysis by APE1 similarly to the effect of the THF residue, which is a well-known analog of the AP site, and this allowed us to use such AP DNAs to imitate DNA with particular types of clustered damages. PARP1, isolated and in cell extracts, efficiently interacted with AP DNA with analogs of AP sites producing a Schiff base. PARP1 competes with APE1 upon interaction with AP DNAs, decreasing the level of its cross-linking with AP DNA, and inhibits hydrolysis of AP sites within AP DNAs containing DEG and THF residues. Using glutaraldehyde as a linking agent, APE1 is shown to considerably decrease the amount of AP DNA-bound PARP1 dimer, which is the catalytically active form of this enzyme. Autopoly(ADP-ribosyl)ation of PARP1 decreased its inhibitory effect. The possible involvement of PARP1 and its automodification in the regulation of AP site processing within particular clustered damages is discussed.
Photoactivated DNA analogs of substrates of the nucleotide excision repair system and their interaction with proteins of NER-competent extract of HeLa cells. Synthesis and application of long model DNA by A. N. Evdokimov; I. O. Petruseva; P. E. Pestryakov; O. I. Lavrik (157-166).
Long linear DNA analogs of nucleotide excision repair (NER) substrates have been synthesized. They are 137-mer duplexes containing in their internal positions nucleotides with bulky substitutes imitating lesions with fluorochloroazidopyridyl and fluorescein groups introduced using spacer fragments at the 4N and 5C positions of dCMP and dUMP (Fap-dC- and Flu-dU-DNA) and DNA containing a (+)-cis-stereoisomer of benzo[a]pyrene-N2-deoxyguanidine (BP-dG-DNA, 131 bp). The interaction of the modified DNA duplexes with the proteins of NER-competent HeLa extract was investigated. The substrate properties of the model DNA in the reaction of specific excision were shown to vary in the series Fap-dC-DNA << Flu-dU-DNA < BP-dG-DNA. During the experiments on affinity modification of the proteins of NER-competent extract, Fap-dC-DNA (137 bp) containing a 32P-label in the photoactive nucleotide demonstrated properties of a highly efficient and selective probe. The set of the main targets of labeling included polypeptides of the extract with the same values of apparent molecular weights (35–90 kDa) as when using the shorter (48 bp) Fap-dC-DNA. Besides, some of the extract proteins were shown capable of specific and effective interaction with the long analog of NER substrate. Electrophoretic mobility of these proteins coincided with the mobilities of DNA-binding subunits of XPC-HR23B and PARP1 (∼127 and T]115 kDa, respectively). The 115-kDa target protein was identified as PARP1 using NAD+-based functional testing. The results suggest that the linear Fap-dC-DNA is an unrepairable substrate analog that can compete with effective NER substrates in the binding of the proteins responsible for lesion recognition and excision.

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