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  • br Roles of TLS polymerases outside DNA damage tolerance


    Roles of TLS polymerases outside DNA damage tolerance
    Preparing the ground for more DNA damage: adaptive responses through gene induction
    Conclusions and perspectives Although known for many decades, the relevance of TLS in genome stability is normally considered secondary to mechanisms that effectively remove DNA damage. However, the existence of so many TLS polymerases, with the intricate mechanisms that guarantee damage tolerance, challenges this notion. As an important paradox, though naturally error-prone, these proteins provide us strong protection against mutagenesis, and cancer, as exemplified by the high incidence of tumors in XP-V patients. Most of the known functions for these TLS processes come from UV-induced lesions, but other types of DNA lesions are replicated in the human genome, and relatively little is still understood on how, and which, TLS polymerase(s) participate for helping the pannexin-1 inhibitor to cope with them. For example, endogenous DNA lesions are identified as responsible for the aging process [240,241], and little is known on how they are naturally replicated in proliferating tissues. As discussed above, the same is true for non-canonical DNA structures, and it will not be a surprise if specific mechanisms are identified for their replication. Besides, DNA lesions are also important blocks for RNA transcription machinery, with fundamental importance for cell killing and aging [242]. Possibly those transcription blocks form structures of RNA/DNA hybrids, such as the known R-loops, which are certainly more complex to replicate than simple DNA lesions [243,244]. An important and current question is whether cells have a way to replicate such structures, or whether this is a lethal collision. Even for more “classic” lesions such as photoproducts, several basic questions are still open and deserve more investigation. For example, it would be important to understand the relative roles of gaps induced on the lagging strand, compared to the participation of novel repriming polymerase on the leading strand. Another interesting issue is how Pol ζ is recruited to perform gap filling, if this occurs behind the fork, independent from S-phase and from the whole replication machinery, including PCNA and accessory proteins that function close to the fork. Moreover, the SOS-like adaptive system observed in human cells is potentially mutagenic, but its relevance for carcinogenesis is not completely understood. Also, as most anti-cancer therapy relies on the use of DNA damage inducing agents, the knowledge of how the induced lesions are replicated may help to understand how tumor cells evade and survive treatment. In fact, as tumor cells are fast replicating, compared to normal tissues, one would expect that the TLS polymerases will develop key roles on cells replicating their damaged genome, thus a basic mechanism for chemotherapy resistance. Therefore, TLS polymerases would be relevant targets for the development of inhibitors, for increasing the killing power of chemotherapeutic drugs, specifically for the tumor cells, hopefully preserving normal tissues, as suggested very recently [245]. Concluding, although recent data have filled some of our knowledge gaps in how replication of some lesions occur, unraveling the replication stress responses and specifically TLS mechanisms in human cells is still a long road to go.
    Acknowledgments This work was supported by FAPESP, São Paulo, Brazil, (Grants # 2014/15982-6 and 2013/21075-9); CNPq and CAPES (Brasília, DF, Brazil). We thank Dr. Julian Sale (Medical Research Council Laboratory of Molecular Biology, Cambridge, UK) for critical reading of this review.
    Introduction DNA micelles have benefited from the programmable design of nucleic acid ligands and size-controllable hydrophobic assembly of lipid molecules. As such, they have been widely developed as an efficient tool in biochemical research with numerous applications, such as intracellular imaging, targeted drug delivery, and immune response initiation. However, even after several years of development, accurate structural profiling of DNA micelles has not been achieved. In spite of the unparalleled properties of such exquisite structures, critical micelle concentration (CMC) remains a limiting factor that militates against expanded applications of DNA micelles,5, 6 a challenge shared by all kinds of micellar materials. Meanwhile, since hydrophobic forces exist widely in bilayer structures and biological environments, DNA micelles can be easily degraded upon incubation with cells. As a consequence, part of the DNA-lipid monomer may insert on the cell surface such that only a small number of micelles are able to traverse the bilayer by a fusion and shedding process to finally function inside the cell. This could be solved by stabilizing intra-micelle interactions by crosslinking each monomer of a DNA micelle. One approach is using Hoogsteen hydrogen bonding to crosslink lipid monomers by forming a G-quadruplex in the presence of potassium ions.4, 8 Compared with hydrogen bonding, a more stable crosslinking strategy is to use covalent bonds.9, 10, 11 However, such a solution, as demonstrated in most reported methods thus far, is thwarted by extended time investment, sophisticated synthesis of monomer required, or unsatisfactory stability improvement.