Abstract
BRCA1/2 are tumor suppressor genes controlling genomic stability also at telomeric and subtelomeric loci. Their mutation confers a predisposition to different human cancers but also sensitivity to antitumor drugs including poly(ADP-ribose) polymerase (PARP) inhibitors and G-quadruplex stabilizers. Here we demonstrate that BRCA2 deletion triggers TERRA hyperexpression and alternative lengthening mechanisms (ALT) in colon cancer cells in presence of telomerase activity. This finding opens the question if cancer patients bearing BRCA2 germline or sporadic mutation are suitable for anti-telomerase therapies, or how ALT activation could influence the short or long-term response to anti-PARP inhibitors or anti-G-quadruplex therapies.
Highlights
Telomeres are nucleoprotein structures at the end of eukaryotic chromosomes preserving genome integrity [1]
Telomere homeostasis is affected by BRCA1/2 mutations as a consequence of global increase of genomic instability, due to alteration of DNA repair pathways, and for direct implication of BRCA2 in telomere replication [24,25,26]
It has been recently demonstrated that BRCA1/2 mutations in patients and BRCA1 silencing in cancer cell lines correlated with telomeric structural alterations such as hypomethylation of subtelomeric regions, increase of DDR
Summary
Telomeres are nucleoprotein structures at the end of eukaryotic chromosomes preserving genome integrity [1]. They consist of species-specific CG-rich repeats, (TTAGGG)n in humans, and exhibit heterochromatic marks [2,3]. Cancer cells reactivate telomere maintenance mechanisms (TMM), which in the majority of cases consist of reactivation of the telomerase holoenzyme, a retrotranscriptase which add repeats to DNA ends by using an RNA template [8]. ALT positivity of cancer cells is more difficult to be assessed than telomerase positivity since a series of different parameters have to be considered: high and heterogeneous telomeres length, presence of ALT-associated PML bodies (APBs), and presence of DNA circles containing telomeric repeats as refuse of homologous recombination [11]. ALT positivity is associated with alteration of expression of chromatin remodeling factors with subtelomeric
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