Mitochondrial dna damage, repair, degradation and experimental approaches to studying these phenomena. The recently discovered mammalian dna glycosylaseap lyases, neil1 and neil2, unlike the. Age and tissuespecific changes in mitochondrial and nuclear dna base excision repair activity in mice. Uracil excision repair is ubiquitous in all domains of life and initiated by uracil dna glycosylases udgs which excise the promutagenic base, uracil, from dna to leave behind an abasic site apsite. This damage is mitigated primarily by the base excision repair ber pathway, one of the few dna repair pathways with confirmed activity on mitochondrial dna. Genes and junk in plant mitochondriarepair mechanisms and. Jul 01, 2009 mitochondrial dna is thought to be especially prone to oxidative damage by reactive oxygen species generated through electron transport during cellular respiration. Base excision repair ber of dna corrects a number of spontaneous and environmentally induced genotoxic or miscoding base lesions in a process initiated by dna glycosylases. Through genetic epistasis analysis of the yeast saccharomyces cerevisiae. In the present study, we investigated the presence of. Mitochondrial dna is frequently exposed to oxidative damage, as compared to nuclear dna. In contrast to the situation for nuclear ber, we find no evidence for long patch.
Singlenucleotide and longpatch base excision repair of. It has been shown that dna repair in the mitochondrion proceeds through both short and longpatch base excision repair ber. Dna2, a helicasenuclease family member, plays versatile roles in processing dna intermediates during dna replication and repair. Ber is initiated by a dna glycosylase that recognizes and removes the damaged base, leaving an abasic site that is further processed by short patch repair or long patch repair that largely uses different proteins to complete ber. T1 long patch base excision repair in mammalian mitochondrial genomes. This was followed by a report of mitochondrial repair of o 6.
Long patch base excision repair in mammalian mitochondrial genomes by bartosz szczesny, anne w. A limited number of mitochondrial repair enzymes involved in base excision. Base excision repair ber corrects dna damage from oxidation. Ap sites, which are among the most frequent dna damages in mammalian cells, have long been considered to be repaired exclusively via the base excision repair ber pathway. This is a journal and virtual library useful to scientists, physicians and patients. Long patch base excision repair in mammalian mitochondrial genomes article pdf available in journal of biological chemistry 28339. Sep 20, 2012 mitochondrial dna is essential, but for many years mammalian mitochondria were thought to lack repair systems for their dna. Long patch base excision repair in mammalian mitochondrial genomes.
All mammalian dna glycosylases that remove uracil are monofunctional. There is some evidence that oxidized bases such as 8oxoguanine 8oxog, one of the most abundant base lesions induced by ros, could also be repaired by nucleotide excision repair ner, the other major excision repair pathway, as shown in vivo in yeast, and in an in vitro assay with mammalian cellfree extract containing ner proteins. Repair of the resulting apsites requires an apendonuclease, a dna polymerase, and a dna ligase whose combined activities result in either shortpatch or longpatch repair. Dna polymerase beta participates in mitochondrial dna repair.
Mitochondrial dna repair mechanisms, in particular the base excision repair. Jan 21, 2009 base excision repair ber is the primary dna repair pathway that corrects base lesions that arise due to oxidative, alkylation, deamination, and depurinat ber facilitates the repair of damaged dna via two general pathways shortpatch and longpatch. Evidence that msh1p plays multiple roles in mitochondrial. Dna damage and base excision repair in mitochondria and their. The related nucleotide excision repair pathway repairs bulky helixdistorting lesions. Long patch base excision repair in mammalian mitochondrial genomes by bartosz. Much of the damage is the result of spontaneous decay of dna lindahl 1993, although similar damage may also be caused by environmental chemicals, radiation, or treatment with cytostatic drugs. Sep 26, 2008 long patch base excision repair in mammalian mitochondrial genomes bartosz szczesny, anne w. Base excision repair ber is a cellular mechanism, studied in the fields of biochemistry and genetics, that repairs damaged dna throughout the cell cycle. The role of dna repair in maintaining mitochondrial dna stability. Base excision repair of dna in mammalian cells sciencedirect. Ap endonucleaseindependent dna base excision repair in.
Mitochondrial genomes accumulate mutations approximately one order of magnitude. Although mismatch repair activity is present in mammalian mitochondria, it appears. Ber and longpatch ber, whereas dna ligase 3 is essential in mitochondria gao et al. Such damage typically results from deamination, oxidation, or methylation. Mitochondrial dna is thought to be especially prone to oxidative damage by reactive oxygen species generated through electron transport during cellular respiration. In mammalian cells, processing of ap sites generated after excision is carried out either by single. The cellular dna repair pathway known as baseexcision repair is responsible for removing toxic base lesions and strand breaks from genomic and mitochondrial dna. At least 11 distinct mammalian dna glycosylases are known, each recognizing a few related lesions, frequently with some overlap in specificities.
Chromatin structure, replication, dna damage repair. B are generally absent, except in egg and sperm cells. It is responsible primarily for removing small, nonhelixdistorting base lesions from the genome. It has been shown that dna repair in the mitochondrion proceeds through both short and long patch base excision repair ber. Ber is important for removing damaged bases that could otherwise cause mutations by mispairing or lead to breaks in dna during replication. The mission of the national institute of environmental health sciences is to discover how the environment affects people in order to promote healthier lives. Mammalian mitochondria contain multiple small genomes. Although the mammalian organelle possesses almost all known nuclear dna repair pathways, including base excision. Sankar mitra professor of radiation oncology, full member.
Selected publications national institute of environmental. Alternatively, the longpatch ber pathway produces a repair tract of at least two nucleotides. In mammalian cells, processing of ap sites generated after excision is carried out either by singlenucleotide replacement or by longpatch dna synthesis fortini and dogliotti, 2007. Singlenucleotide patch base excision repair of uracil in dna by.
The major pathway for correcting oxidatively damaged dna in both the nuclear and the mitochondrial genomes is the berssb repair. Fen1 stimulation of dna polymerase beta mediates an excision step in mammalian long patch base excision repair. Although the mammalian organelle possesses almost all known nuclear dna repair pathways, including base excision repair, mismatch repair and recombinational repair, the proximity of mtdna to the main sites of ros production and the lack of protective histones may result in increased susceptibility to various types of mtdna damage. This is easily understood if dna repair in genes is accomplished by accurate mechanisms, whereas less accurate mechanisms including nonhomologous end joining or breakinduced replication are used in nongenes. Mismatch repair activity in mammalian mitochondria. Mitochondrial dna damage induced autophagy, cell death. The mitochondrial genomic material mtdna, similarly to nuclear genome. Dna repair activity in mammalian mitochondria is base excision repair ber. Mitochondrial base excision repair of uracil and ap sites takes place by singlenucleotide insertion and long patch dna synthesis. Uracil excision repair in mycobacterium tuberculosis cell. Longpatch ber processing of a dna lesion is more complex than spber. Base excision repair ber corrects small base lesions that do not significantly distort the dna helix structure.
The mitochondrial form of dna ligase iii is the only dna ligase activity. Deficiency in repair of the mitochondrial genome sensitizes. Base excision repair is a cellular mechanism, studied in the fields of biochemistry and genetics, that repairs damaged dna throughout the cell cycle. Mitochondrial dna encodes a set of polypeptides and is subjected to constant oxidative stress due to ros production within the organelle. Mitochondrial dna damage induced autophagy, cell death, and. The ber pathway is initiated by one of many dna glycosylases, which recognize and catalyze the removal of damaged bases. Ber takes place by short patch repair or long patch repair that largely use different proteins downstream of the base excision.
The site contains medical and biology information as articles, databases, books, lectures and more. We have investigated whether mammalian cells can repair pyrimidine dimers in their mitochondrial dna which have been induced by ultraviolet light. Szczesny b1, tann aw, longley mj, copeland wc, mitra s. Early steps in the dna base excisionsingle strand interruption repair pathway in mammalian cells. Oct 02, 2010 base excision repair ber pathway, protects both nuclear and mitochondrial dna from spontaneous dna damage, mainly generated by eactive oxigen spices ros produced by the normal metabolism of. Through genetic epistasis analysis of the yeast saccharomyces. Base excision repair of dna in mammalian cells request pdf.
Rosinduced dna lesions, including oxidized bases, abasic ap sites, and oxidized ap sites, cause dna strand breaks and are repaired via the base excision. Human dna2 is a mitochondrial nucleasehelicase for efficient processing of dna replication and repair intermediates. The mitochondrial dna polymerase in health and disease. Repair of damaged bases and ap sites involving 1nucleotide incorporation, named single nucleotide snber, was observed with mitochondrial and nuclear extracts. Base excision repair cold spring harb perspect biol. Yeast dna2 ydna2 is essential in rna primer removal during nuclear dna replication and is important in repairing uv damage, base damage, and doublestrand breaks. Long patch base excision repair in mammalian mitochondrial genomes szczesny, b. Base excision repair short patch full hd base excision repair ber pathway, protects both nuclear and mitochondrial dna from spontaneous dna damage, mainly generated by eactive. This was followed by a report of mitochondrial repair of o 6ethyl2deoxyguanosine myers et al. The assay system is based upon the ability of the phage t4 uv endonuclease to nick covalently closed circular mitochondrial dna that contain pyrimidine dimers. The cellular dna repair pathway known as base excision repair is responsible for removing toxic base lesions and strand breaks from genomic and mitochondrial dna. The site also contains the forms to search the most useful sites on the web.
Wilsonfen1 stimulation of dna polymerase beta mediates an excision step in mammalian long patch base excision. Long patch base excision repair in mammalian mitochondrial genomes downloading may take up to 30 seconds. The mitochondrial genome is a matrilineally inherited dna that. Mitra s 2008 long patch base excision repair in mammalian mitochondrial genomes. Base excision repair ber is the predominant and best understood dna. Mitra, long patch base excision repair in mammalian mitochondrial genomes, journal of. Choreography of oxidative damage repair in mammalian genomes. Further studies are warranted to establish repair patch size in mitochondrial lpber. The paradigm for repair of oxidized base lesions in genomes via the base excision repair ber pathway is based on studies in escherichia coli, in which ap endonuclease ape removes all 3. The mitochondrial genome is highly susceptible to damage by reactive oxygen species ros generated endogenously as a byproduct of respiration. Base excision repair europe pmc article europe pmc.
Deficiency in repair of the mitochondrial genome sensitizes proliferating myoblasts to oxidative damage. Such base lesions cause little distortion to the dna helix structure. Learn vocabulary, terms, and more with flashcards, games, and other study tools. The lesions induced by reactive oxygen species in both nuclear and mitochondrial genomes include altered bases, abasic ap sites, and singlestrand breaks, all repaired primarily via the base excision repair ber pathway. Base excision repair ber is a critical genome defense pathway that deals with a broad range of nonvoluminous dna lesions induced by endogenous or exogenous genotoxic agents. Removal of oxidative dna damage via fen1dependent longpatch base excision repair in human cell mitochondria. Susceptibility of skeletal muscles to oxidative injury. In contrast, they also rearrange and expand frequently. Previously, we have shown that while microhomologymediated end joining can account for dna deletions in mitochondria, classical nonhomologous dna end joining, the predominant doublestrand break dsb repair pathway in nucleus, is undetectable. However, the repair of oxidized deoxyribose fragments at the 5. Ber is a complex process initiated by the excision of the damaged base, proceeds through a sequence of reactions that generate various dna intermediates, and culminates with restoration of the original dna structure. Copeland, and sankar mitra, 1 department of biochemistry and molecular biology, university of texas medical branch, galveston, texas 77555 and the niehs, national institutes of health.
Dna damage and base excision repair in mitochondria and. Plant mitochondrial genomes have very low mutation rates. Base excision repair and lesiondependent subpathways for repair of oxidative dna damage. Ber is a complex process initiated by the excision of the damaged base, proceeds through a sequence of reactions that generate various dna intermediates, and culminates with restoration of the original. Aug 30, 2019 base excision repair ber is a critical genome defense pathway that deals with a broad range of nonvoluminous dna lesions induced by endogenous or exogenous genotoxic agents. Fen1 in the nucleus, resulting in multinucleotide repair patch long patch lpber. Rosinduced dna lesions, including oxidized bases, abasic ap sites, and oxidized ap sites, cause dna strand breaks and are repaired via the base excision repair ber pathway in both the nucleus and mitochondria. The maintenance of mitochondrial dna integritycritical analysis. Mitochondrial dna is essential, but for many years mammalian mitochondria were thought to lack repair systems for their dna. Mitochondrial base excision repair of uracil and ap sites takes place by singlenucleotide insertion and longpatch dna synthesis.
A new role of dna polymerase beta in mitochondrial base. Membrane association of mitochondrial dna facilitates base. Base excision repair ber was the first identified repair pathway in mitochondria, in yeast and humans, and remains the best characterized 3338. Mitochondrial base excision repair can proceed via two pathways, singlenucleotideber snber or longpatch ber lpber copeland and longley, 2008. Mitochondrial dna repair mechanisms, in particular the base excision repair pathway, constitute an important mechanism for maintenance of mitochondrial dna integrity. Long patch base excision repair in mammalian mitochondrial genomes bartosz szczesny, anne w. Long patch base excision repair in mammalian mitochondrial.
Base excision repair ber pathway, protects both nuclear and mitochondrial dna from spontaneous dna damage, mainly generated by eactive oxigen spices ros produced by the normal metabolism of. Singlenucleotide and longpatch base excision repair of uracil and abasic sites in dna by arabidopsis cell extracts. Now it is well established that base excision repair serves a key role. Our results show that dimers are not removed from the mitochondrial dna of mouse l cells. At the moment, there is reasonably solid evidence showing that the short and long patch base excision repair ber pathways exist in mitochondria 282930 31. The role of dna repair in maintaining mitochondrial dna. While these organelles have efficient base excision removal of oxidative dna lesions and alkylation damage, many dna repair systems that work on nuclear dna damage are not active in mitochondria. Mitochondria contain their own genome organized into dnaprotein complexes, called mitochondrial nucleoids, along with multiprotein machineries, which promote mitochondrial dna mtdna replication, transcription and repair. Mitochondria lack nucleotide excision repair, and the presence of doublestrand. With either repair pathway, an oxidized or damaged base is recognized and cleaved by a specific glycosylase, leaving an abasic site that is cleaved on the 5. Our data demonstrate that, surprisingly, human dna2 hdna2 does not localize to nuclei, as it lacks. The absence of a pyrimidine dimer repair mechanism in.
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