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PubMed1985

Formation of unique arylamine:DNA adducts from 2-aminofluorene activated by prostaglandin H synthase.

Prostaglandin H synthase in the presence of arachidonic acid catalyzes the peroxidative metabolism of 2-aminofluorene (2-AF) to an electrophile(s) which binds covalently to calf thymus DNA in vitro. Moreover, this electrophile(s) appears distinct from the classical 2-AF-derived electrophiles, N-hydroxy-2-AF and the 2-AF nitrenium ion. Both the prostaglandin H synthase:arachidonic acid and horseradish peroxidase:hydrogen peroxide systems were used to investigate the binding of [3H]-2-AF to DNA and the nature of the DNA adducts formed from peroxidative activation of 2-AF. Modification of DNA by N-hydroxy-2-AF under mildly acidic conditions was used as a reference system in these studies and yielded a single 2-AF:nucleoside adduct, identified as N-(deoxyguanosin-8-yl)-2-AF (C8-dGuo-AF). Enzymatic hydrolysis of DNA modified by 2-AF activated in either of the peroxidase systems liberated 2-AF:nucleoside adducts that differed considerably from C8-dGuo-AF in chromatographic and extraction properties. C8-dGuo-AF from DNA hydrolysates was easily extracted into n-butyl alcohol and adsorbed by Sephadex LH-20 columns. In contrast, the peroxidase-derived adducts were poorly extracted into n-butyl alcohol and were not retained on Sephadex LH-20 columns. Experimental evidence suggests the peroxidase-derived adducts may possess a negative charge at neutral pH. Since C8-dGuo-AF is the only 2-AF:nucleoside adduct formed when 2-AF is activated via N-hydroxylation, these new adducts represent a marker unique to peroxidative activation of 2-AF. Therefore, 2-AF:DNA adducts can be used as a differential end point with which to assess the relative roles of N-hydroxylation and peroxidation in the metabolic activation of 2-AF in cell culture and in target tissues in vivo.

Animals↗
PubMed1993

Simultaneous incorporations of two anticancer drugs into DNA. The structures of formaldehyde-cross-linked adducts of daunorubicin-d(CG(araC)GCG) and doxorubicin-d(CA(araC)GTG) complexes at high resolution.

Anthracycline antibiotics (notably daunorubicin (DAU) and doxorubicin (DOX)) and nucleoside analog arabinosylcytosine (araC or aC) are important anticancer drugs. They are sometimes used together in the treatment of certain cancers. Both classes of compounds act by blocking DNA replication and transcription. To probe whether both drugs can be incorporated simultaneously into DNA and the possible structural consequences, we carried out x-ray diffraction analyses of the complexes between DAU/DOX and araC-containing DNA hexamers cross-linked with formaldehyde. The crystal structures were determined to high resolution (DAU-CGaCGCG, 1.2 A, space group P4(1)2(1)2, R = 0.182, 3275 reflections; DOX-CAaCGTG, 1.5 A, space group C2, R = 0.175, 3359 reflections), and they are similar to those of the previously studied DAU- and DOX-DNA complexes, despite different crystal packings. Two DAU/DOX molecules intercalate at both ends of the helix with their amino sugars in the minor groove. As in the structure of DAU-CGCGCG (Wang, A.H.-J., Gao, Y.-G., Liaw, Y.-C., and Li, Y.K. (1991) Biochemistry 30, 3812-3815), a covalent methylene bridge (from formaldehyde) between the N3' of daunosamine and the N2 of the guanine is formed in both adducts. In DOX-CAaCGTG, the two halves are slightly different with a root-mean-square deviation of 0.322 A between them. The O14 hydroxyls of the intercalated DOXs are within hydrogen bond distances to the O2P atoms of the A2p(aC3) and A8p(AC9) steps. The O2'-hydroxyl group from araC does not affect the binding of DAU-DOX or the conformation of the drug-DNA complexes. The results suggest that three major drug modifications on DNA, i.e., intercalation, covalent bond formation, and nucleoside analog incorporation, can coexist in the same DNA molecule without difficulty. When they occur in close proximity in DNA, they may provide an additive inhibitory effect for the target enzymes.

Base Sequence↗
PubMed1986

N6-methyldeoxyadenosine residues at specific sites decrease the activity of the E1A promoter of adenovirus type 12 DNA.

The activity of eukaryotic promoters is highly sensitive to site-specific modifications by DNA methylations. We have used the E1A promoter of adenovirus type 12 (Ad12) DNA to investigate the effects of methylations at different promoter sites on its activity. The chloramphenicol acetyltransferase gene has served as an activity indicator. Activity of the E1A promoter is lost or markedly decreased by deoxycytidine methylation of two HpaII (5'-C-C-G-G-3') or seven HhaI (5'-G-C-G-C-3') sites upstream from the 3' located T-A-T-A signal. There are two T-A-T-A signals in the E1A promoter of adenovirus type 12 DNA, one T-A-T-T-A-T sequence starting at nucleotide 276 (5' located), a second T-A-T-T-T-A-A sequence starting at nucleotide 414 (3' located). Deoxycytidine methylations at two AluI (5'-A-G-C-T-3') sites downstream from the 5' located T-A-T-A signal have no effect on promoter activity. When one EcoRI (5'-G-A-A-T-T-C-3') or one TaqI (5'-T-C-G-A-3') sequence at 281 base-pairs upstream or 61 base-pairs downstream from the 5' located E1A T-A-T-A signal, respectively, is deoxyadenosine methylated, the promoter becomes inactive. Deoxyadenosine methylation at one MboI (5'-G-A-T-C-3') site, which is located 127 nucleotides downstream from the 5' located T-A-T-A signal, fails to decrease E1A promoter activity. There is no conspicuous anatomical relation of any of these sites to the two presumptive enhancer sequences in the E1A promoter. We conclude that 5-deoxymethylcytidine or N6-methyldeoxyadenosine residues have to be introduced at highly specific promoter sites to inactivate the promoter. These sites are probably different for different promoters.

Adenoviridae↗
PubMed2005

Nutrition and aberrant DNA methylation patterns in atherosclerosis: more than just hyperhomocysteinemia?

Methylation is a reversible modification of DNA participating in epigenetic regulation of gene expression. It is now clear that atherosclerosis is associated with aberrant DNA methylation patterns in the vascular tissue and peripheral blood cells, but the origin of this anomaly is poorly understood. Based on evidence that global DNA hypomethylation coexists with hyperhomocysteinemia in advanced human atherosclerosis, it is widely assumed that altered DNA methylation patterns in atherosclerosis are mainly secondary to a decrease in factors essential for the synthesis of S-adenosyl methionine (SAM, the main methyl group donor in DNA methylation reactions), such as folate and vitamin B-12, or to homocysteine-induced blocking of SAM biosynthesis. Nonetheless, recent work expanded this view by showing that both local DNA hyper- and hypomethylation occur in early atherosclerosis in normohomocysteinemic mice and that atherogenic lipoprotein profiles promote DNA hypermethylation in cultured human macrophages. These findings suggest that during early atherosclerosis, nutritional factors affect DNA methylation patterns by mechanisms that are likely to be independent of vitamin or homocysteine levels. These data have the potential to assist in the identification of preventive or therapeutic avenues for cardiovascular disease.

Arteriosclerosis↗
PubMed2002

Chemical aspects of clustered DNA damage induction by ionising radiation.

Ionising radiation induces a variety of chemical modifications to DNA, ranging from simple, isolated lesions to clustered DNA damage, in which two or more lesions are formed within a few tens of base pairs by a single radiation track. Multiple lesions, e.g. tandem lesions and amplification of damage, may also be induced in DNA by reaction with a single hydroxyl radical. It has been proposed from biophysical modelling that clustered DNA damage is less repairable and therefore contributes to the biological severity of ionising radiation. In this review, some evidence is presented which indicates that non-double strand break (non-DSB) clustered DNA damage is induced in significant yield, relative to that of DSBs, in mammalian cells. Enzymatic processing of clustered DNA damage in synthetic oligonucleotides has been shown to be compromised, depending on the nature of the lesions present. The role of clustered DNA damage in the early stages of the development of radiation-induced carcinogenesis remains to be addressed.

Animals↗
PubMed1986

In situ hybridization of an acetylaminofluorene-modified probe recognized by Z-DNA antibodies in vitro.

An in situ hybridization procedure, based on the chemical modification of DNA by acetylaminofluorene (AAF), followed by a specific immunoreaction was used to localize a Z-DNA sequence isolated from the satellite DNA of Cebus appella. The AAF probe is localized on the R-band-positive heterochromatic segments of Cebus chromosomes, which strongly react with Z-DNA antibodies. The use of a nonradioactive single-stranded labeled probe confirms the reliability and the rapidity of immunochemical methods for the detection of DNA sequences on chromosomes.

2-Acetylaminofluorene↗
PubMed1986

[Chemical carcinogens and DNA, covalent binding and chemical modifications].

Chemical carcinogenic agents are usually metabolized into final metabolites susceptible to be DNA bound to form adducts. They may also modify DNA bases. Binding may be studied in vitro in the presence of an enzyme system causing the formation of final metabolites or in vivo. Because of the small amount of adducts formed in vivo, they can only be visualized with radioactive compounds or with a 32P marking technique after DNA hydrolysis. A limit of detection of adduct for 10(8) nucleotides has thus been reached for polycyclic compounds. The covalent binding index enables to quantify this binding. The consequences of DNA alterations vary according to the substitutes. In the case of acetyl-aminofluorene, they lead to mutations by shifting of the reading frame (frameshift). Alkylations lead to inaccurate pairing causing pin point mutations or depurinations.

Carcinogens↗
PubMed1998

Overexpression of stably transfected human glutathione S-transferase P1-1 protects against DNA damage by benzo[a]pyrene diol-epoxide in human T47D cells.

The (+)-anti enantiomer of benzo[a]pyrene-7,8-dihydrodiol-9, 10-epoxide (BPDE) is a potent mutagenic and carcinogenic metabolite of benzo[a]pyrene (BP), and a major fraction is conjugated with glutathione in vivo. The chemopreventive role of glutathione S-transferases (GSTs) in protecting against covalent modification of DNA and other cellular macromolecules by BPDE was modeled in human T47D and MCF-7 cell lines previously stably transfected with human GSTpi1 (hGSTP1). Cells were exposed to [3H]BPDE (30-600 nM). Dose-response experiments indicated that the high level of expression of hGSTP1-1 in the T47Dpi cell line (4411 +/- 183 milliunits/mg of cytosolic protein, using 1-Cl-2,4-dinitrobenzene as substrate), resulted in 70-90% reduction in the covalent 3H-adduct formation in DNA or RNA isolated from the GSTP1-transfected T47Dpi cell line. The lower level of hGSTP1-1 expression in the transfected MCF-7 cell line (91 milliunits/mg) provided only marginal protection against [3H]BPDE adduct formation and did not affect sensitivity to BPDE-induced cytotoxicity. Protection against BPDE-induced cytotoxicity was observed only in the T47Dpi cell line, which had an IC50 value 5.8-fold greater than that of the T47Dneo control cell line. Measurement of glutathione conjugates of BPDE indicated that the total conjugation was 5-fold higher in the GSTpi-transfected T47D line, most of which was exported into the culture medium over the 20-min exposure period. These results indicate that hGSTP1-1 protects effectively against DNA and RNA modification by BPDE, but moderate to high level expression may be required for strong protection against BPDE-induced genotoxicity and cytotoxicity.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed2001

Evidence for horizontal transfer of SsuDAT1I restriction-modification genes to the Streptococcus suis genome.

Different strains of Streptococcus suis serotypes 1 and 2 isolated from pigs either contained a restriction-modification (R-M) system or lacked it. The R-M system was an isoschizomer of Streptococcus pneumoniae DpnII, which recognizes nucleotide sequence 5'-GATC-3'. The nucleotide sequencing of the genes encoding the R-M system in S. suis DAT1, designated SsuDAT1I, showed that the SsuDAT1I gene region contained two methyltransferase genes, designated ssuMA and ssuMB, as does the DpnII system. The deduced amino acid sequences of M. SsuMA and M.SsuMB showed 70 and 90% identity to M.DpnII and M.DpnA, respectively. However, the SsuDAT1I system contained two isoschizomeric restriction endonuclease genes, designated ssuRA and ssuRB. The deduced amino acid sequence of R.SsuRA was 49% identical to that of R.DpnII, and R.SsuRB was 72% identical to R.LlaDCHI of Lactococcus lactis subsp. cremoris DCH-4. The four SsuDAT1I genes overlapped and were bounded by purine biosynthetic gene clusters in the following gene order: purF-purM-purN-purH-ssuMA-ssuMB-ssuRA++ +-ssuRB-purD-purE. The G+C content of the SsuDAT1I gene region (34.1%) was lower than that of the pur region (48.9%), suggesting horizontal transfer of the SsuDAT1I system. No transposable element or long-repeat sequence was found in the flanking regions. The SsuDAT1I genes were functional by themselves, as they were individually expressed in Escherichia coli. Comparison of the sequences between strains with and without the R-M system showed that only the region from 53 bp upstream of ssuMA to 5 bp downstream of ssuRB was inserted in the intergenic sequence between purH and purD and that the insertion target site was not the recognition site of SsuDAT1I. No notable substitutions or insertions could be found, and the structures were conserved among all the strains. These results suggest that the SsuDAT1I system could have been integrated into the S. suis chromosome by an illegitimate recombination mechanism.

Amino Acid Sequence↗
PubMed2005

Effect of the psoralen-based photochemical pathogen inactivation on mitochondrial DNA in platelets.

Photochemical treatment (PCT) of platelet concentrates, using amotosalen HCl and UVA-light, inactivates pathogens by forming adducts between amotosalen and nucleic acids. The impact of the photochemical treatment on pathogens and leukocytes has been studied extensively. Yet little is known about the effect of PCT on nucleic acids in platelets. Platelets contain viable mitochondria and mitochondrial DNA (mtDNA) and this study aimed at evaluating the amotosalen modifications on platelet mtDNA. We applied two independent but complementary molecular assays to investigate qualitative as well as quantitative aspects of the psoralen-mediated DNA modifications in platelet mtDNA. The amotosalen-DNA modification density was measured using (14)C-labeled amotosalen. Amotosalen (150 microM) yielded 4.0 +/- 1.2 psoralen adducts per 1,000 bp in mtDNA after irradiation with 3 J/cm(2) UVA. Furthermore, we tested if the PCT-induced DNA modifications could be detected by a PCR assay. On the basis of PCR inhibition due to amotosalen-DNA adducts, mtDNA-specific PCR assays were developed and tested for their specificity and sensitivity. Our data revealed that mtDNA in platelets is substantially modified by PCT and that these modifications can be documented by a PCR inhibition system.

Blood Platelets↗
PubMed1988

[Complementary addressed modification of single- and double-stranded DNA by alkylating derivatives of oligonucleotides isolated by partial DNA fragmentation].

Reagents for complementary addressed modification of nucleic acids are proposed to be synthesized on the base of oligonucleotides obtained by partial chemical fragmentation of DNA. The alkylating 4-(N-2 chlorethyl-N-methylamino) benzyl-5'-phosphamide derivatives of 5'-[32P]-labelled oligonucleotides obtained from single and double-stranded DNA cloned in bacteriophage M13 mp9 have been synthesized. The alkylated derivatives of oligonucleotides selectively modify the complementary tracts of single-stranded DNA-target. They are also able to modify the complementary regions in double-stranded supercoiled plasmid DNA.

Alkylating Agents↗
PubMed1999

The HaeIV restriction modification system of Haemophilus aegyptius is encoded by a single polypeptide.

The HaeIV restriction endonuclease (ENase) belongs to a distinct class of ENases, characterized by its ability to cleave double-stranded DNA on both sides of its recognition sequence, excising a short DNA fragment that includes the recognition sequence. The gene encoding the HaeIV ENase was cloned from Haemophilus aegyptius into pUC19 using a previously described system that does not need the knowledge that a particular ENase is produced by a bacterial strain. DNA sequence analysis of the insert contained on this plasmid identified a single open reading frame (ORF), with the predicted protein having an apparent molecular mass of approximately 110 kDa. The protein encoded by this ORF was purified to homogeneity from Escherichia coli strain ER1944 carrying the haeIVRM gene on a recombinant plasmid under the control of the inducible ara promoter. The protein possessed both ENase and methyltransferase (MTase) activities. Amino acid sequence analysis was able to identify several conserved motifs found in DNA MTases, located in the middle of the protein. The enzyme recognizes the interrupted palindromic sequence 5' GAPyNNNNNPuTC 3', cleaving double-stranded DNA on both strands upstream and downstream of the recognition sequence, releasing an approximately 33 bp fragment. The ENase possessed an absolute requirement only for Mg(+2). ATP had no influence on ENase or MTase activities. The ENase made the first strand cleavage randomly on either side of the recognition sequence, but the second cleavage occurred more slowly. The MTase activity modified symmetrically located adenine residues on both strands within the recognition sequence yielding N6-methyl adenine. Furthermore, the MTase was active as a dimer.

Adenosine Triphosphate↗
PubMed2000

DNA interactions of antitumor cisplatin analogs containing enantiomeric amine ligands.

Modifications of natural DNA and synthetic oligodeoxyribonucleotide duplexes in a cell-free medium by analogs of antitumor cisplatin containing enantiomeric amine ligands, such as cis-[PtCl(2)(RR-DAB)] and cis-[PtCl(2)(SS-DAB)] (DAB = 2,3-diaminobutane), were studied by various methods of molecular biophysics and biophysical chemistry. These methods include DNA binding studies by pulse polarography and atomic absorption spectrophotometry, mapping of DNA adducts using transcription assay, interstrand cross-linking assay using gel electrophoresis under denaturing conditions, differential scanning calorimetry, chemical probing, and bending and unwinding studies of the duplexes containing single, site-specific cross-link. The major differences resulting from the modification of DNA by the two enantiomers are the thermodynamical destabilization and conformational distortions induced in DNA by the 1,2-d(GpG) intrastrand cross-link. It has been suggested that these differences are associated with a different biological activity of the two enantiomers observed previously. In addition, the results of the present work are also consistent with the view that formation of hydrogen bonds between the carbonyl oxygen of the guanine residues and the "quasi equatorial" hydrogen of the cis amine in the 1, 2-d(GpG) intrastrand cross-link plays an important role in determining the character of the distortion induced in DNA by this lesion.

Amines↗
PubMed1989

Ecori DNA methylase activity is eliminated upon histidine residue modification.

The E. coli EcoRI DNA methylase activity is completely eliminated in five minutes upon incubation with the histidine residue specific reagent diethyl pyrocarbonate. In that two moles of N-ethoxyformylimidazole per mole of methylase are detected spectroscopically upon inactivation and activity is not restored by hydroxylamine, it is likely that activity loss is due to double modification of a single histidine residue. This information is critical in determining the enzymatic mechanism, causes of the pH-activity curve, designing protein mutants and interpreting previous structure-function data.

Chemical Phenomena↗
PubMedDate not supplied

Hypomethylation of cytosine 5-methyltransferase in human neoplasms.

Cytosine methylation is an epigenetic modification of DNA involved in control of gene expression. Neoplastic cells exhibit various alterations both in DNA methylation and activity of the enzyme responsible for this modification, 5-methyltransferase (5-MeTase). As there is little requirement for 5-methyltransferase expression in normal cells except during mitosis, we argued that the gene would be hypermethylated in normal cells. Southern analysis revealed almost complete methylation of the gene in genomic DNA from the peripheral blood leukocytes of healthy subjects and a primary fibroblast derived cell line. In contrast, in DNA from a range of tumour tissues and tumour derived cell lines, 5-MeTase exhibited marked hypomethylation. The results of this study indicate that dysregulation of the DNA methylating machinery, especially with respect to the methylation status of 5-MeTase, is a feature of a wide range of neoplasms.

Blotting, Southern↗
PubMed1984

[Effect of O-hydroxylamine on the transforming DNA from Bacillus subtilis. Correlation of chemical modifications with genetic consequences].

The action of methoxyamine (MA) on B. subtilis transforming DNA (50 degrees C, pH 4,5 and 6,0, 1 M MA) was studied. The rate of cytosine residues modification in DNA is 250 times less than in monomer (rate constants for DNA are 1,5 X 10(-1) min-1 at pH 4,5, and 2,5 X 10(-6) min-1 in the first 300 hours of treatment at pH 6,0). At pH 4,5 the rates of cytosine (I) conversion into N4-methoxycytosine (II) and into 6-methoxyamino-5,6-dihydro-N4-methoxycytosine (III) are constant (II/III ratio is about 2,1). At pH 6,0 the II/III ratio smoothly increases from 1,0 to 1,6 (200 and 900 hours of treatment) due to a decrease in the product III accumulation rate. The frequency of MA-induced mutations shows a bell-shaped dependence on time with maxima (approximately 10%) at 80 (pH 4,5) and 500 (pH 6,0) hours of treatment. In both cases approximately 10% of cytosine residues are modified. These results suggest that either compound III is efficiently removed from the transforming DNA, or its presence does not arrest the DNA replication.

Bacillus subtilis↗
PubMed1987

The binding efficiency of polyclonal and monoclonal antibodies to DNA modified with benzo[a]pyrene diol epoxide is dependent on the level of modification. Implications for quantitation of benzo[a]pyrene-DNA adducts in vivo.

A number of polyclonal antibodies specific for DNA modified with (+/-)trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyre ne (BPDE) were obtained from the sera of New Zealand white rabbits immunized with BPDE-DNA, complexed with methylated bovine serum albumin (mBSA). Monoclonal antibodies were developed by fusion of mouse myeloma cells with spleen cells isolated from BALB/c mice immunized with the same complex of BPDE-DNA and mBSA. These antibodies have been characterized for specificity in a highly sensitive, enzyme-linked immunosorbent assay (ELISA). All antibodies showed a very high affinity for single-stranded BPDE-DNA, but had lower affinity towards native BPDE-DNA. The affinity for the free mononucleoside BPDE-dG was at least 100-fold lower than that for BPDE-DNA, and no affinity was detected for BP tetrols or DNA modified with N-acetoxy-N-acetyl-2-aminofluorene. A high cross reactivity was observed with DNA modified with (+/-)-trans-1,2-dihydroxy-anti-3,4-epoxy-1,2,3,4-tetrahydrochrysene++ +. Using five different antibodies, monoclonal or polyclonal, we observed that the antibody affinity for BPDE-DNA was dependent on the level of modification; in the competitive ELISA as little as 4 fmol BPDE-DNA (50 pmol/micrograms) was sufficient for 50% inhibition with our best antisera, but 17 fmol of the adduct was required when [3H]BPDE-DNA of low modification (1-10 fmol/micrograms) was used as inhibitor. When samples of [3H]BP-DNA isolated from the livers of mice, treated i.p. with different doses of [3H]BP were examined by competitive ELISA and calibrated with [3H]BPDE-DNA of low modification (1-10 fmol/micrograms), binding values calculated from the immunoassay were in good agreement with those obtained from radioactivity measurements. In contrast, when this DNA was quantitated in competitive ELISA using highly modified BPDE-DNA as standards, values by ELISA were 20-40% of those obtained by radioactivity. These results indicate that the use of serially diluted BPDE-DNA of high modification as standard competitor in the ELISA will lead to erroneous results in the measurement of adducts in DNAs modified to a low extent (biological samples). The property of antisera specific for BP-DNA, recognizing highly modified DNA more efficiently than DNA modified to a low extent, may be common to all antisera elicited against highly modified DNA immunogens. Therefore we conclude that antibody affinity must be tested also with DNA samples of low modification, obtained either in vitro or in vivo.

2-Acetylaminofluorene↗
PubMedDate not supplied

Age-dependent modulation of DNA repair enzymes by covalent modification and subcellular distribution.

Chronic oxidative stress is generally believed to be a major etiologic factor in the aging process. In addition to modulation of signaling processes and oxidation of cellular proteins and lipids, reactive oxygen species (ROS) induce multiple damages in both nuclear and mitochondrial genomes, most of which are repaired via the DNA base excision repair pathway. 8-Oxoguanine (8-oxoG), a major ROS product in the genome, is excised by 8-oxoG-DNA glycosylase (OGG1) and the resulting abasic (AP) site is cleaved by AP-endonuclease (APE1) in the initial steps of repair. Here, we provide data showing that differences between young and aged cells' efficiency in import of OGG1 and APE1 may be responsible for age-associated increase in DNA damage in both nuclear and mitochondrial compartments. It is also evident that age-dependent changes in covalent modifications of APE1 by acetylation regulate its action as a transcriptional repressor of many Ca(2+)-responsive genes by binding to nCaRE, in addition to its endonuclease activity. Thus, ROS-induced altered signaling is responsible for age-dependent changes in post-translational modifications and import of DNA repair enzymes into nuclei and mitochondria (mt), which in turn affect repair of their genomes.

Aging↗