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We cannot take responsibility for items which are lost or damaged in transit. For purchases where a shipping charge was paid, there will be no refund of the original shipping charge. Publisher Description. The low-to-moderate sensitivity of the NER mutants suggest a less critical contribution of NER to survival following chronic exposure [ 94 ]. Thus, it seems that the requirement of repair genes in S. Interestingly, the requirement of repair gene to mitigate the cytotoxic effect of formaldehyde following acute high dose exposure 60 mM, 15 min differed significantly from that following chronic low-dose exposure to formaldehyde 1.

However, the molecular mechanism underlying the change in the major repair pathway upon acute high-dose exposure remains to be elucidated.

DNA repair mechanism - Base excision repair

Although it is not clear whether relevant to the aforementioned observations with yeast, it has been shown that the concentration and the regimen of formaldehyde treatment affect the formation of DPCs and gene expression in human cells, and that the genes with altered expression are involved in detoxification but not DPC repair [ 95 ].

It has been demonstrated very recently that the metalloprotease Wss1 in S. The mutants deficient in Wss1 were found to accumulate DPCs. Proteins homologous to Wss1 are present in bacteria and several eukaryotes such as fungi, plants, Plasmodium , and Trypanosoma brucei , but are absent in animals [ 97 ].

DNA Damage and Repair: Volume III: Advances from Phage to Humans (Contemporary Cancer Research)

Consistent with the results with yeast [ 96 ], recent analysis of in vitro DNA replication using Xenopus egg extracts has shown that the proteolytic degradation of DPCs in leading and lagging strands promotes replication through lesion sites []. The chicken B lymphocyte cell line DT40 has a high rate of gene targeting and has been used as a model system for reverse genetics studies in higher eukaryotes [ 99 ].

The genes involved in the repair of DPCs have been elucidated by assessing the formaldehyde sensitivity of DT40 cells with targeted mutations in various DNA repair genes [ ]. Higher eukaryotes use multiple pathways for ICL repair, and the existence of the specialized FA pathway represents a significant difference from yeasts. Accordingly, one possible interpretation of the data with DT40 cells is that formaldehyde simultaneously induces DPCs and ICLs, and that the two lesions are repaired via partially overlapping pathways. As mentioned in Section 4.

These results indicate that cell survival after treatment with formaldehyde and azadC reagents is mainly conferred by the HR pathway. The sensitivity of FA-pathway-deficient mammalian cells to formaldehyde has also been examined. It remains to be seen whether the response of mammalian cells to formaldehyde through the FA pathway is species dependent [ ].

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These in vivo observations with mammalian cells contrast with those observed with E. Together these observations indicate that the upper size limit of cross-linked proteins amenable to mammalian NER is around 8 kDa in vitro , which is notably smaller than that for bacterial NER Fig.


The smaller upper size limit of DPCs for mammalian NER accounts for a less critical contribution of NER to cell survival after treatment with formaldehyde and azadC observed in mammalian cells see above. Despite significant differences in protein components, bacterial and mammalian NER shares an activity optimum for a cross-linked protein size of around 1.

It would be interesting to know whether this is simply due to a mechanistic reason or if it has some evolutional significance. In this model cross-linked proteins are initially degraded to short peptides by the proteasome, and due to the robust activity of mammalian NER for DPCs containing short peptides in vitro , the resulting DNA-peptide cross-links are removed by NER Fig. Polyubiquitination targets proteins for recognition and degradation by the 26S proteasome [ ].

However, it was shown that cross-linked proteins were not polyubiquitinated in vivo after treatment with formaldehyde, and hence were not subjected to proteasomal degradation in cells [ 32 ].

DNA Damage and Repair: Advances from Phage to Humans by Jac A. Nickoloff

Very recently the yeast metalloprotease Wss1 and a putative protease in Xenopus egg extracts have been shown to be involved in the repair of DPCs [ 96 , ]. It would be interesting to elucidate whether the functional homologs are present in mammalian cells, although no clear orthologs of Wss1 seem to exist in mammalian cells see Section 4.

Indeed, the formation of RAD51 nuclear foci, which is reminiscent of HR, was observed following treatment with formaldehyde and azadC [ 32 ]. When CHO cells are treated with replication inhibitors such as hydroxyurea and aphidicolin, accumulation of DSBs due to fork breakage is observed even in HR-proficient cells [ , ], suggesting mechanistic differences in the formation of DSBs by DPCs and replication inhibitors.

However, whether they are also involved in fork breakage at DPCs remains to be elucidated. Mouse embryonic stem cells deficient in two major DNA glycosylases Nth1 and Ogg1 did not exhibit significant sensitivity to formaldehyde and azadC Ide et al. ICLs are also repaired by the replication-independent mechanism involving structure-specific endonucleases and TLS polymerases [ ].

The replication-independent repair of DPCs will be important for the survival of nonproliferating cells such as neurons since it ensures faithful gene expression and maintains cellular homeostasis. Some types of DPC generated by chemical and physical agents are stable and are not spontaneously reversed Section 3.

Thus, a significant portion of DPCs persist in the genome and can affect various aspects of DNA transactions such as replication, transcription, repair, and recombination.

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The replicative helicases unwind the parental double-stranded DNA into two single strands, and DNA polymerases synthesize leading and lagging strands in continuous and discontinuous modes, respectively, using the separated strands as templates. The mechanism is well conserved from phages and bacteria through to higher organisms [ , ]. The replisome proceeds through the barrier of DNA-associated proteins such as nucleosomes and site-specific DNA-binding proteins.

The replicative helicases disrupt nucleosomes in eukaryotes, probably with the aid of histone modifications and chaperones [ ].

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  • Thus, the replisome has an intrinsic capacity to proceed through the protein barrier as long as it is reversible. The effects of DPCs on replication were studied in vitro using host-cell reactivation assays. These studies revealed that DPCs inhibit the replication of plasmids, indicating that the progression of the replisome is impeded by DPCs in vivo. Analysis of the replication intermediates of plasmids containing DNMT-DPCs by two-dimensional gel electrophoresis and electron microscopy suggests that replication can switch from the theta to the rolling circles mode after a replication fork is stalled by a DNMT-DPC [ ].

    A study involving plasmids containing histone fragments as DPCs revealed that the efficiency of replication in E. With plasmids containing T4 endonuclease V as a DPC, the efficiency of replication is dependent on the uvrD gene [ ]. The impediment of the replisome by DPCs is more closely associated with replicative helicases that unwind DNA at the front of the replication fork than with replicative polymerases.

    Replicative helicases such as the phage T7 gene 4 protein T7gp4 , simian virus 40 large T antigen Tag , and E. The eukaryotic replicative helicase also assembles into a ring-shaped heterohexamer of minichromosome maintenance Mcm proteins 2—7 [ ]. In addition, a subcomplex comprised of Mcm4, Mcm6, and Mcm7 Mcm forms a ring-shaped heterohexamer containing two respective subunits and exhibits helicase activity in vitro [ ].

    DPCs in the translocating strand, but not those in the nontranslocating strand, were found to impede the progression of the T7gp4, Tag, DnaB, and Mcm helicases a conflicting result with Tag has been reported, [ ]. The impediment varied with the size of the cross-linked proteins, with a threshold size for clearance of 5. In addition, the results obtained for helicase suggest the distinct fates of replisomes upon encountering conventional bulky damage and large DPCs.

    Conventional bulky damage both in the translocating and nontranslocating strands are cleared by helicases and arrest DNA polymerase Fig. This can further lead to functional uncoupling of polymerases and helicases as well as that of leading and lagging polymerases. DPCs in the translocating strand block the helicase, immediately halting leading- and lagging-strand synthesis Fig.

    This will preclude functional uncoupling of polymerases and helicases and of leading and lagging polymerases. In contrast, DPCs in the nontranslocating strand do not block the helicase, and act like conventional bulky damage. Accordingly, the mechanism underlying stalled fork-processing and the concurrent events of damage signaling may differ significantly for DPCs in the translocating and nontranslocating strands. The scheme is drawn for eukaryotic replication, where the replicative helicase translocates on the leading template strand [].

    Stalled DnaB, T7gp4, and Mcm helicases exhibit limited stability and dissociate from DNA with a half-life of 15—36 min in vitro [ ]. With E. The dissociation of stalled DnaB from DNA accounts at least partially for the inactivation of the replisome in vitro. The inactivation of the replisome due to loss of DnaB also seems to be consistent with the finding that reactivation of a stalled replication fork requires reloading of DnaB or replication machinery via the PriA helicase in E.

    In yeast, replisomes stalled by tight but reversible DNA—protein complexes are stable in vivo , and DNA synthesis continues through the barriers after a transient pause ca. Thus, Mcm is likely to be retained in the stalled replisome in yeast cells. In contrast, a recent study of in vitro replication of plasmids with Xenopus egg extracts has shown that Mcm7 a component of the Mcm complex dissociates from DNA with an approximate half-life of 10 min when progression of the replisome is blocked by an ICL [ ]. It is possible that the replisome can proceed by gradually disrupting reversible protein roadblocks in cells while retaining the helicase in the replisome. Conversely, this does not occur if the replisome is completely arrested by irreversible roadblocks such as DPCs and ICLs. Viral, prokaryotic, and eukaryotic RNA polymerases RNAPs have an ability to transcribe through nucleoproteins and site-specific DNA binding proteins, although the read-through efficiencies vary depending on the roadblocking proteins [ ].

    ATP-dependent chromatin remodeling complexes, histone chaperones, and covalent histone modifications promote the transcription through nucleosomes [ ]. It has also been shown that the trailing RNAP stimulates forward translocation of the stalled leading RNAP through reversibly bound proteins [ , ], as well as through naturally occurring pausing sites [ , ].

    Resolution of the crystal structure of yeast RNAP II revealed that conventional bulky lesions such as a cyclobutane pyrimidine dimer, a cisplatin intrastrand cross-link, and a monofunctional platinum adduct in the TS are delivered to the active site or its proximal position and then arrest transcription [ - ]. Luciferase-based reporter assays are widely used as a tool to study gene expression at the transcriptional level.

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    The pGL4. The luciferase activity was found to decrease with increasing amounts of cross-linked histone H1 protein, indicating that transcription of the luciferase gene by RNAPII was inhibited by DPCs in vivo Fig. T7 RNAP is a single subunit RNAP and is structurally unrelated to bacterial and eukaryotic multisubunit RNAPs, but all share many functional characteristics in the initiation and elongation phases of transcription [ ]. There was trend for the number of copies of runoff transcripts to decrease for larger DPCs.

    It was also found that when DPCs are present in the NTS, no damage-dependent abortive transcripts are produced, although common weak abortive products form for all templates. Base substitutions, insertions, and deletions [minus signs — ] in transcripts are highlighted in red, green, and blue, respectively [].

    Interestingly, sequence analysis of runoff transcripts has shown that stalled leading and trailing T7 RNAPs become highly error prone and generate untargeted mutations in the upstream intact template regions Fig. This contrasts with the transcriptional mutations induced by conventional DNA lesions, which are delivered to the active site or its proximal position in RNAPs and cause direct misincorporation.

    Accordingly, similar cooperating mechanism may be working for transcription through DPCs. DPCs are superbulky DNA lesions that affect replication, transcription, and repair via mechanisms that differ from those involving conventional bulky lesions. The findings from in vitro studies are summarized below. In DNA replication, DPCs, unlike conventional bulky lesions, block the progression of the replicative helicase and constitute helicase blocks when they are located in the translocating strand. Conversely, DPCs in the nontranslocating strand do not block the helicase.