Effects of BRCA2 deficiency on telomere recombination in non-ALT and ALT cells

We observed a significant increase in T-SCE frequencies in four BRCA2 defective human cell lines thus suggesting that BRCA2 suppresses recombination at telomeres. To test this hypothesis further we analyzed T-SCE frequencies in a set of Chinese hamster cell lines with or without functional BRCA2. Our results indicate that introduction of functional BRCA2 normalizes frequencies of T-SCEs thus supporting the notion that BRCA2 suppresses recombination at telomeres. Given that ALT (Alternative Lengthening of Telomeres) positive cells maintain telomeres by recombination we investigated the effect of BRCA2 depletion in these cells. Our results show that this depletion causes a dramatic reduction in T-SCE frequencies in ALT positive cells, but not in non-ALT cells.BRCA2 suppresses recombination at telomeres in cells that maintain them by conventional mechanisms. Furthermore, BRCA2 depletion in ALT positive cells reduces high levels of T-SCEs normally found in these cells. Our results could be potentially important for refining telomerase-based anti-cancer therapies.Telomeres are specialized nucleo-protein structures involved in chromosome end protection. This protective function requires an intricate coordination between the mechanisms that maintain telomere structure and DNA damage response mechanisms [1]. The importance of the above coordination is highlighted by the fact that defects in numerous DNA damage response proteins have acute effects on telomere maintenance mechanisms. Selected examples include proteins such as Ku and DNA-PKcs involved in DNA double strand break (DSB) repair by non-homologous end joining (NHEJ) [2], ATM, a protein responsible for DNA damage signalling [3], MRN, a complex consisting of MRE11, RAD50 and NBS proteins responsible for DSB sensing [4] and ERCC1/XPF responsible for nucleotide excision repair (NER) [5].Two recent studies revealed another DNA damage response protein that affects telomere maintenance, namely BRCA2 [6,7]. BRCA2 associates