The reliance of NHEJ on DNA-PKcs has prompted the assessment of DNA-PKcs mutants or small molecule inhibitors of DNA-PKcs on HDR following DSB induction – events that have been reported to increase HDR rates [ 20].
Recent studies have shown that inhibition of the expression level or function of survivin and/or XIAP with anti-sense RNA, short interfering RNA (siRNA), dominant-negative mutants, or small molecules induces apoptotic cell death in tumor cells but not in normal cells.
These mutant classes include eggshell-defective mutants, sterile or small brood-producing mutants, mutants with delayed progression through S phase, and mutants with normal early embryonic cell divisions but highly penetrant lethality presumably due to defects later in embryogenesis.
Regardless of the specific strategies for generating mutants, mutant large or small subunits could be expressed in E. coli along with a wild-type version of the other subunit, the relevant complex purified, and the properties of the enzyme determined to allow the impact of the mutations to be studied.
Our data strongly support the possibility that the activated Stat3 pathway could serve as a therapeutic target in cervical and possibly in endometrial cancers using a dominant-negative Stat3 mutant or small molecular inhibitors.
A similar redistribution of mATG9 from its normal perinuclear localization close to the plasma membrane was seen in cells overexpressing a dominant-negative dynamin mutant or small interfering RNA (siRNA) to the clathrin adaptor AP2 (to block clathrin-dependent endocytosis).
We have previously shown that single wrky18, wrky40 and wrky60 mutants exhibited no or small alterations in response to the hemibiotrophic bacterial pathogen P. syringae or the necrotrophic fungal pathogen B. cinerea [ 27].
Our data strongly support that the activated Stat3 pathway could serve as a therapeutic target in rhabdomyosarcoma and osteosarcoma cancers using a dominant negative Stat3 mutant or a small molecule Stat3 inhibitor, STA-21.
Experimental evidence suggests that mutant protein monomers or small oligomers rather than large insoluble protein aggregates are the most toxic species in neurodegenerative polyQ diseases 9. Additionally, impairment of the protein clearance machinery due to ageing or oxidative stress 10 and failure to degrade misfolded polyQ proteins cause earlier disease initiation.
Specifically, mutants with small or large mean size were not significantly overrepresented in the group of mutants with a high G1 DNA content (ρ = −0.09).
Infection for 2, 3, 4 and 6 h with the espB mutant was associated with no, or small, changes in the asymmetric distribution of IL-8 levels between both apical and basolateral compartments.
