Abstract
Some cancer cells elongate their telomeres through the ALT (alternative lengthening of telomeres) pathway, which is based on homologous recombination for the addition of telomere repeats without telomerase activity. General control non-derepressible 5 (GCN5) and P300/CBP-associated factor (PCAF), two homologous lysine acetyltransferases, exert opposite effects on the ALT pathway, inhibiting or favoring it respectively. Here we show that ALT cells are particularly sensitive to the inhibition of acetyltransferases activities using Anacardic Acid (AA). AA treatment recapitulates the effect of PCAF knockdown on several ALT features, suggesting that AA decreased the ALT mechanism through the inhibition of lysine transferase activity of PCAF, but not that of GCN5. Furthermore, AA specifically sensitizes human ALT cells to radiation as compared to telomerase-positive cells suggesting that the inhibition of lysine acetyltransferases activity may be used to increase the radiotherapy efficiency against ALT cancers.
Highlights
Some cancer cells counteract the telomere attrition occurring through cell division not by activating telomerase but through the ALT pathway
We have previously shown that the knockdowns of the two homologous lysine acetyl transferases General control nonderepressible 5 (GCN5) and P300/CBP-associated factor (PCAF) had opposite effects on the alternative mechanism of telomere maintenance, suggesting that PCAF, which is absent from telomeres may indirectly favor ALT, whereas GCN5, which is present at telomeres, may oppose to telomere recombination [13]
We report that the pan-inhibitor of lysine acetyl transferases Anacardic Acid (AA) recapitulates only the effects of PCAF knockdown on ALT cells
Summary
Some cancer cells counteract the telomere attrition occurring through cell division not by activating telomerase but through the ALT (alternative lengthening of telomeres) pathway. ALT is based on homologous recombination for the addition of telomere repeats [3]. Telomeres of ALT cells are highly heterogeneous in length, ranging from undetectable to extremely long [4]. ALT cells contain specialized promyelocytic leukemia (PML) nuclear bodies termed ALT-associated PML bodies (APBs), which are thought to be the main sites of telomere elongation in ALT cells. APBs contain usual PML nuclear bodies components like PML and Sp100 along with telomeric DNA, telomere binding proteins, and a mixture of DNA replication, recombination and repair factors [5, 6]. ALT cells are characterized by the presence of abundant linear and circular extrachromosomal telomere repeats (ECTR) [7, 8]. The ALT telomeres are submitted to a high level of post-replicative exchanges known as telomeresister chromatid exchanges (T-SCEs) [9]
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