Synthetic lethality

Nasmyth In the yeast, most of the cleavage takes place in a Polo mutant, and the centromeres go to the poles quite normally. But the chromosomes don t fully disengage. We suspect about 10% of the Sccl may not be coming off. If you make a Pdsl /Polo double mutant (which is difficult because they are almost synthetic lethal), then it looks like there isn t much anaphase at all. But these are recent, preliminary results. 

SYNTHETIC LETHALITY OF INHIBITING PARP-1 AND PARP-2 IN BRCA MUTANT TUMORS... 

Moreover, the CSN is involved in checkpoint control. The double deletions of csnl and csn2 mutants crossed with checkpoint pathway mutants such as rad3, chk, and cdsl are synthetically lethal in S. pombe [52]. Cdsl kinase is constitutively activated in csnl mutants. Similarly, loss of csn5 in Drosophila results in activation of Mei-41, one of the ATM/ATR family kinases involved in meiotic checkpoint upon DNA damage [90]. 

Kaelin WG Jr (2005) The concept of synthetic lethality in the context of anticancer therapy. Nat Rev Cancer 5 689-698... 

Azorsa DO, Gonzales IM, Basu CD et al (2009) Synthetic lethal RNAi screening identifies sensitizing targets for gemcitahine therapy in pancreatic cancer. J Transl Med 7 43... 

Whitehurst AW, Bodemann BO, Cardenas J et al (2007) Synthetic lethal screen identification of chemosensitizer loci in cancer cells. Nature 446 815-819... 

PARP Inhibition as a Prototype for Synthetic Lethal Screens... 

Key words Synthetic lethal screen, DNA repair, PARP, BRCA, BER, HR... 

PARP Inhibition Is Synthetic Lethal in Cancer Cells Deficient in BRCA 1/2... 

Fig. 2. Synthetic lethal interaction between BER and FIR. BER and FIR are DNA repair pathways for SSB and DSB, respectively. Inhibition of BER or FIR alone does not cause cell death, while simultaneous inhibition of BER and FIR results in cell death.

The synthetic lethal effect between PARP inhibition and BRCAl/2 deficiency was first described in 2005 by Farmer et al and Bryant et al in preclinical studies (17, 18). BRCAl/2 deficient cell lines are more sensitive to PARP inhibition than BRCAl/2 proficient cell lines in colony formation assays and in xenograft models (17, 18). BER and HR are DNA repair pathways that carry out the repair of SSB and DSB, respectively. Inhibition of either pathway alone is not lethal, but loss of both pathways causes cell death (Fig. 2). Mechanistically, PARP inhibition blocks the activity of BER and leads to DNA SSB accumulation inside cells. When cells enter the next round of DNA replication, these DNA SSBs are converted to DNA DSBs which can be efficiently repaired through... 

Synthetic Lethal Screen of Small Molecule Compound Library... 

Activating Ras mutations have been found in more than 25% of human tumors. However, a drug-like small molecule inhibitor for Ras protein is not currently available. Several synthetic lethal screens have been carried out using isogenic cell lines for Ras. Torrance et al. conducted a synthetic lethal screen of a library of about 30,000 compounds and identified some novel hits including... 

Synthetic Lethal Screen ofshRNA/ siRNA Libraries... 

In addition, synthetic lethal screens can also be used to identify potential biomarkers for a known drug or compound. In a recent siRNA screen, Wiltshire et al. carried out a study to identify genes... 

Lucchesi JC (1968) Synthetic lethality and semi-lethaHty among functionally related mutations of Drosophila melano aster. Genetics 59 37-14... 

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