DNA Repair: a Single-Edged Sword?

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Can C er models of cancer with short hairpin hairpin short with cancer of models groups combined tractable both mutagenesis, and response tigate the role of TLS in therapy (a TLS scaffold protein). To inves and REV1 DNA polymerase-ζ) of TLS include REV3L (a subunit of chemotherapeutics. Components by caused those as such lesions, DNA bulky to bypass synthesis polymerases use error-prone mechanism whereby alternative DNA mutagenesis in tumours to therapy but can also keep can not only sensitize chemoresistant sion of translesion synthesis (TLS) always a double-edged sword: repres DNA repair mechanisms is not recent papers suggest that targeting of accelerated mutagenesis. Two typically accompanied by the threat However, DNA repair inhibition is with certain DNA repair defects. strategy for the treatment of cancers or can function as a synthetic lethal sitize cancer cells to chemotherapy inhibition of DNA repair can sen chemotherapy response. Therapeutic modulate both tumorigenesis and Deficiencies in DNA repair processes A single-edged sword? cisplatin markedly sensitized NSCLC cells to cancer (NSCLC). REV3L knockdown mouse model of non-small-cell lung down REV3L in a Hemann and colleagues knocked of chemorefractory tumours, Mike also increase the therapeutic response tigate whether TLS repression could crosslinking agent cisplatin. To inves further sensitized lymphomas to the knock down of REV3L or REV1 lymphoma model and showed that used a chemosensitive of TLS components. depletion RNA (shRNA)-mediated

DNA R Graham Walker and colleagues TLS is a DNA damage tolerance in vitro in EPAIR

mouse mouse

–/– –/– - -

- - of TLS following chemotherapy treat of the survival the tumour progression and prolonged REV3L knockdown slowed NSCLC of the the lung and allowed assessment injected into the tail vein colonized age. shRNA-transduced NSCLC cells persistence of unrepaired DNA dam possibly owing to fewer mutations. emergence of therapeutic resistance, ment, REV1 knockdown delayed the following successive rounds of treat either alkylating agent, cyclophosphamide, were not immediately sensitized to an REV1 NSCLC cells treated with cisplatin. was evident in REV3L in mutagenesis on TLS suppression to 6 therapy treatment, result in resistance ( guanine phosphoribosyl transferase tions at the mouse hypoxanthine mutagenesis assay, in which muta ment, both groups used a cellular Neil Smith Hprt To investigate the mutagenic role - thioguanine (6 ) locus, ) acquiredlocus, during chemo - in vivo in in vitro in downregulated lymphomas therapeutic response — or or in vivo in

mice. - Resea TG). A reduction - downregulated . However,.

- - R - - - ch highlights toxicity of a TLS-targeted agent targeted therapeutics. The potential using systemic delivery of TLS- gene knockdown can be replicated the effects of cancer cell-specific TLS mutagenesis. somal instability and thus promoting replication forks, leading to chromo Rev3l cells that can tolerate the loss of TLS, other studies have shown that, in of therapeutic response. However, TLS could be a crucial determinant Therefore, the mutagenic effect of DNA repair deficiencies. cancer cells with oftypes particular inhibition can be selectively lethal to it remains to be whether seen TLS in REV3L absence of obvious viability defects embryonic lethal, in contrast to the of out knock as be considered and carefully balanced, towards normal cells would need to USA acquired chemoresistance. Error-prone translesion synthesis mediates ORIGINAL RESEARCH PAPERS 20786–20791 (2010) chemotherapy. Pol Suppression of Rev3, the catalytic subunit of It be will interesting to whether see ζ , sensitizes drug-resistant lung tumors to

107 deletion causes the collapse of , 20792–20797 (2010) Vo - knockdown cells. Finally, L Proc. Natl Acad. Sci. USA u ME Rev3l 11 11 in mice is Proc. Natl Acad. Sci. | j Darren J. | Doles, J., AN Xie, K., u AR

107 et al. et al.

Burgess y ,

2011