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Keywords: chromatin, repair, nucleosome, histone, DNA, DNA breaks, oxidative stress, RNA polymerase ..... Nouspikel, T. and Hanawalt, P.C., DNA repair in ter.
ISSN 00963925, Moscow University Biological Sciences Bulletin, 2015, Vol. 70, No. 3, pp. 122–126. © Allerton Press, Inc., 2015. Original Russian Text © N.S. Gerasimova, N.A. Pestov, O.I. Kulaeva, D.V. Nikitin, M.P. Kirpichnikov, V.M. Studitsky, 2015, published in Vestnik Moskovskogo Universiteta. Biologiya, 2015, No. 3, pp. 21–25.

MOLECULAR BIOLOGY

Repair of Chromatinized DNA N. S. Gerasimovaa, N. A. Pestovb, O. I. Kulaevaa, D. V. Nikitina, M. P. Kirpichnikova, and V. M. Studitskya a

Department of Biology, Moscow State University, Moscow, 119992 Russia email: [email protected] b Ogarev Mordovian State University, Saransk, 430000 Russia Received February 6, 2015

Abstract—Endogenous and exogenous agents generate tens of thousands of lesions in the DNA of every cell daily. The maintenance of correct DNA structure by repair systems is crucial for genome functioning. Eukaryotic nuclear DNA is tightly packaged into chromatin, in which it should be successfully repaired. His torically, it is believed that histones are temporarily removed from the repaired DNA. However, numerous recent studies indicate that the chromatin structure affects the repair response, limiting its distribution, alter ing enzyme activity, and participating in the response choice and restoration of the repaired locus function. Keywords: chromatin, repair, nucleosome, histone, DNA, DNA breaks, oxidative stress, RNA polymerase II, review. DOI: 10.3103/S0096392515030050

The genetic material of a cell is constantly exposed to damaging environmental agents. Ultraviolet radiation covalently links DNA bases inducing the formation of cyclobutane dimers and pyrimidine(64)pyrimidone photoproducts. Ionizing radiation directly causes sin gle and doublestrand DNA breaks and results in pro duction of free radicals. Exogenous and metabolism generated endogenous active chemicals alter canoni cal bases through incorporation of atypical residues, degradation of covalent bonds, etc. The disruption of the DNA structure may also occur in the course of metabolic processes. For example, incorrect nucle otides may be incorporated by DNA polymerase dur ing replication, and the abortive activity of topoi somerases and repair system enzymes may cause DNA breaks. The accumulation of various lesions in the genome leads to the disruption of cell functions and causes mutations, chromosomal aberrations, malig nant degeneration, and apoptosis. All these damages are normally removed from DNA by the enzymes of different repair systems. DNA REPAIR The functionality of the genome is maintained by repair pathways. The repair response depends on the type of damage. In some cases, the initial DNA struc ture is restored in a single enzymatic reaction. For example, in mammalian cells alkyl moieties are removed from position 6 of mutagenic guanine deriv atives by O6methylguanine DNA methyltransferase. However, in most cases, the damaged DNA fragments

are repaired by a complex enzymatic cascade. For example, specific nonbulky lesions and singlestrand breaks are removed by the base excision repair (BER) system. Bulky nucleotide alterations and transcrip tiondisrupting structures trigger the nucleotide exci sion repair (NER) pathway. Replication errors are removed by the mismatch repair (MMR) system. In the case of doublestrand DNA breaks, the most dan gerous DNA lesions, two systems—homologous recombination (HR) and nonhomologous end joining (NHEJ)—are involved in the repair of the DNA structure. Incorrect functioning of any of these repair systems leads to severe metabolic disorders (for more details on the repair systems, see [1, 2]). ORGANIZATION OF NUCLEAR DNA Nuclear DNA is organized into a chromatin—a complex supramolecular structure involving a large number of proteins. Fundamental repeating units of chromatin are nucleosomes—compact structures consisting of DNA and histones. Nucleosome core particle contains a 146bp DNA fragment wrapped around a histone octamer formed by the central tet ramer (H3–H4)2 surrounded by two H2A–H2B dimers [3]. Histones are relatively similar in structure: they consist of two short αhelices and a long central αhelix, which are separated by small bridges. A spe cial role is played by the terminal regions (“tails”) of histones, which most frequently undergo posttransla tional modifications. They are less structured and pro trude beyond the boundaries of the nucleosome core

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particle, which allows them to interact with DNA and proteins [4].

the complex between the repair proteins and DNA (e.g, for the doublestrand breaks [16]).

INTERACTION OF NUCLEOSOMES WITH THE ENVIRONMENT

CHROMATIN REMODELING IN DNA REPAIR

The organization of DNA in the supramolecular structures protects it from many damaging factors. For example, continuous regions of the nucleosomal DNA are inaccessible to nucleases [5, 6]. This shielding applies not only to fairly large enzyme molecules but also to very small agents (e.g., hydroxyl radicals) [7]. Recently, it was shown that the accessibility of DNA may significantly affect the rate of it’s modification [8]. Nucleosomefree genomic regions such as actively transcribed genes remain unprotected, which increases the role of specific repair signaling pathways (for example, transcriptioncoupled NER, TCNER, triggered by the RNA polymerase II at the damaged site). Apparently, the shielding of DNA in chromatin does not protect it only from the direct effect of ultra violet and ionizing radiation [9]. As relative stable complexes, nucleosomes survive even after significant changes in DNA structure [10]. Therefore, the lesions are hidden in chromatin struc ture from damagesensing and DNA repair proteins. Indeed, the DNA in nucleosomes is significantly less accessible to the repair proteins. In nondividing cells, NER proceeds slowly, mostly in the transcribed genes [11]. In moderately transcribed genes that retain nucleosomal structure the repair of photoproducts in nontemplate DNA strand has a specific landscape indicating a less efficient DNA repair in nucleosomes [9]. This can be explained by the theory proposing that sensor proteins detect damages in two steps. At the first step the enzyme weakly and nonnonspecifically binds to the DNA (threedimensional search). At the sec ond step the protein scans along the DNA until the lesion is found (onedimensional search) [12]. Since the ability of the protein to interact with the substrate is described by the binding constant, the determina tion of these constants can help to identify the enzymes that specifically function in the chromatin. For example, it was shown that DNA glycosylase hNTHl recognizes thymine glycols in the chromatin more effectively than its analogue NEIL1 [10, 13]. Thus, the cell presumably contains specific sensory proteins for the chromatin. Furthermore, it was shown that enzymes of the subsequent steps of the repair pathway can improve recognition and even eliminate nucleosomes from DNA [14]. Another enzyme of the BER system, uracilDNA glycosylase, much better binds the uridyl residues directed toward the surface of the nucleosome [15]. In the case of successful recognition of the lesion, the nucleosomal structure prevents the formation of

In early 1990s it was proposed that nucleosomes are removed from DNA at the beginning of the repair response. According to “access–repair–restore” model repair system proteins access nucleosomefree DNA, perform the repair and then chromatin is reas sembled [17]. Later, numerous data confirming the involvement of the chromatinremodeling complexes in the repair response were published [18]. Such complexes are spe cifically recruited to the repair sites in the doublestrand breaks and facilitate DNA repair. The key protein of TCNER, CSB, contains the SWI2/SNF2 domain, which can ATPdependently remodel chromatin after activation by the histone chaperone NAP1 [19]. The stimulation of the doublestrand break repair and NER is also observed in the case of efficient oper ation of histone acetyltransferases (HATs), which are recruited to the repair sites [20–23]. Apparently, his tone acetylation may serve as a signal triggering the chromatin remodeling. For example, in the case of doublestrand DNA breaks, TIP60dependent acety lation of histone H4 near the lesion site is observed. The repair complex is not formed without acetylation. However, the factors that cause chromatin relaxation (hypotonic shock or the treatment of cells with sodium butyrate or chloroquine) restore the functioning of repair proteins. The prerequisite for a successful assembly of the complex and correct location of HR proteins in a damaged locus is the relaxation of chro matin rather than the acetylation of histone H4 [16]. Thus, chromatin, indeed, is a barrier hampering the repair response. Modifying histones and chroma tin remodeling complexes together abolish this barrier, making the repair process possible. It should be noted that, in a highly condensed chromatin, doublestrand DNA breaks are repaired primarily via homologous recombination, and the relaxation of the structure can serve as a signal to switch to this repair pathway. Possibly, chromatin is not a nonspecific barrier for the repair process but functions as a selective structure limiting the response distribution [24]. Repair response to the occurrence of a double strand break only partly depends on the chromatin remodeling activities. For example, the level of phos phorylation of histone H2AX and the activation of the ATMdependent signaling pathway do not depend on the functioning of acetyltransferases. The response to the occurrence of a doublestrand DNA break can be divided into the chromatindependent and chroma tinindependent branches [25].

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SWITCHING THE HISTONE “CODE” DURING DNA REPAIR Interestingly, condensation of relaxed chromatin is required for HR cascade development. This process begins with the dimethylation of histone H3 at posi tion K9 and replacement of H2A with macroN2A1 histone variant [26]. Changes in the complex of posttranslational modi fications and variant forms of histones (the socalled histone “code”) during the repair process are found in an increasing number of cases. Dynamic changes in histone modifications can regulate the choice of the pathway of DNA repair in space and time [27]. Change of histone “code” can be responsible for switch of the cell from the repair response to normal functioning [28, 29]. For example, in the case of activation of the TC NER system, after the restoration of the DNA struc ture, it is necessary to resume the transcription of the repaired site. RNA polymerase II can be removed from the stop site in two ways. In the simplest case the enzyme backtracks upstream and transcription con tinues after the repair is finished. Another option is to degrade RNA polymerase II after ubiquitinylation. In this case, the transcription of the repaired site is resumed by another elongation complex formed on the gene, which has not reached the lesion site in DNA, or such complex is assembled on the promoter de novo. In any case, the start of transcription after repair requires additional chromatin plasticity such as chromatin remodeling and changes in the histone code [19]. Serious hereditary diseases can occur if the cell fails to resume the transcription [30]. It was shown that three chromatinremodeling fac tors—HIRA, FACT, and DotlL—are involved in the stimulation of transcription after the DNA repair [31– 33]. Histone regulator A (HIRA) incorporates histone H3.3 into the transcriptionally active chromatin repaired by the TCNER system. Histone H3.3 may carry specific modifications which serve as a signal to increase the level of transcription [34]. Thus HIRA is not directly involved in the repair process itself but acts as transcription inducing factor [31]. The Spt16 subunit of the heterodimer histone chaperone FACT is involved in the incorporation of new dimers of histones H2A–H2B into the repaired chromatin regions [32]. The exact role of the FACT complex in the resumption of transcription after the repair has not yet been determined. Three ways of this chaperone action are assumed. First of all it can facil itate the upstream translocation and maintenance of RNA polymerase II complex. FACT may also facili tate the transcription of the repaired site. In addition, this chaperone can make the DNA accessible for repair and transcription factors [22, 35]. Both HIRA and FACT are detected at the lesion sites before the repair is completed, and their accumu

lation does not depend on the process of DNA repair itself [31, 32]. Enzyme DOT1L is a subunit of the histone meth yltransferase complex that modifies histone H3 at position K79. Similarly to HIRA, DOT1L does not affect the repair process but it is required for the resumption of stopped transcription. Usually, the transcription of UVdamaged genes is restored in 6– 11 h after exposure and is accompanied by the acetyla tion of histone H4 and DOT1Ldependent H3K79 methylation of the promoter nucleosomes. In the absence of H3K79 methylation, new elongation com plexes are not assembled. Apparently, the methylation of histone H3 at position K79 leads to the relaxation of chromatin on the repressed gene, because its effect can be restored by hyperacetylation of histones [33]. The described traits of transcription resumption are specific only for TCNER pathway and are not observed in other known events of RNA polymerase II stalling. Therefore, a special form of transcription can be suggested for the repaired DNA regions [31, 33]. It remains obscure how the original histone “code” is restored at the repaired sites. It was assumed that the repaired chromatin region can retain variant forms and modifications of histones that are not characteris tic for its functional state and this way carry a certain repair “imprint” even after the complete correction of the DNA structure [24]. Thus, the DNA repair system is a complex network of interacting protein complexes making it possible to readily recognize and eliminate genomic lesions. Through signaling pathways, it is tightly associated with the regulation of the cell cycle and cell metabo lism. For some time, studies were performed with the assumption that DNA is completely released from nucleosomes at the very beginning of the repair pro cess. However, numerous experimental data testify that chromatin proteins are actively involved in the direction and regulation of repair processes. Many important questions in this challenging area of chromatin repair studies are still unrevealed. The ways of effective recognition of lesions in nucleosomes and heterochromatin, the functions of modifications and variant forms of histones, the restoration of the original histone “code,” and many other issues remains incomplete. Since the problems of DNA repair are the key issues for understanding the mecha nisms of carcinogenesis, development of severe genetic diseases and aging, further development of this area is interesting from both basic and practical stand points. ACKNOWLEDGMENTS This study was supported by the Russian Science Foundation (project no. 142400031).

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Translated by M. Batrukova

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