Alternative lengthening of human telomeres is a conservative DNA replication process with features of break‐induced replication. (19th October 2016)

• Record Type: Journal Article
• Authors: Roumelioti, Fani‐Marlen; Sotiriou, Sotirios K; Katsini, Vasiliki; Chiourea, Maria; Halazonetis, Thanos D; Gagos, Sarantis
• Is Part Of: EMBO reports. Volume 17:Number 12(2016:Dec.)
• Page Start: 1731
• Page End: 1737
• Publication Date: 2016-10-19
• Subjects: alternative lengthening of telomeres -- break‐induced replication -- PolD3 -- PolD4 -- telomere length regulation; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.201643169
• Languages: English
• ISSNs: 1469-221X

Abstract

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 (DSBs) 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. Synopsis: Human cells that rely on ALT to maintain telomere length use break‐induced replication, a DNA repair pathway associated with conservative rather than semiconservative DNA replication. Telomeres of human ALT cells are replicated conservatively. PolD3 and PolD4, two subunits of DNA polymerase delta that function in break‐induced replication, are needed for the maintenance of telomere length and function in human ALT cells. Abstract : Human cells that rely on ALT to maintain telomere length use break‐induced replication, a DNA repair pathway associated with conservative rather than semiconservative DNA replication.