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Alternative lengthening of human telomeres is a conservative DNA replication process with features of break‐induced replication
Author(s) -
Roumelioti FaniMarlen,
Sotiriou Sotirios K,
Katsini Vasiliki,
Chiourea Maria,
Halazonetis Thanos D,
Gagos Sarantis
Publication year - 2016
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201643169
Subject(s) - replication (statistics) , telomere , dna replication , origin recognition complex , genetics , biology , pre replication complex , replication factor c , microbiology and biotechnology , control of chromosome duplication , eukaryotic dna replication , dna , virology
Abstract Human malignancies overcome replicative senescence either by activating the reverse‐transcriptase telomerase or by utilizing a homologous recombination‐based mechanism, referred to as alternative lengthening of telomeres ( ALT ). In budding yeast, ALT exhibits features of break‐induced replication ( BIR ), a repair pathway for one‐ended DNA double‐strand breaks ( DSB s) that requires the non‐essential subunit Pol32 of DNA polymerase delta and leads to conservative DNA replication. Here, we examined whether ALT in human cancers also exhibits features of BIR . A telomeric fluorescence in situ hybridization protocol involving three consecutive staining steps revealed the presence of conservatively replicated telomeric DNA in telomerase‐negative cancer cells. Furthermore, depletion of PolD3 or PolD4, two subunits of human DNA polymerase delta that are essential for BIR , reduced the frequency of conservatively replicated telomeric DNA ends and led to shorter telomeres and chromosome end‐to‐end fusions. Taken together, these results suggest that BIR is associated with conservative DNA replication in human cells and mediates ALT in cancer.