Abstract
Loss of telomere protection occurs during physiological cell senescence and ageing, due to attrition of telomeric repeats and insufficient retention of the telomere-binding factor TRF2. Subsequently formed telomere fusions trigger rampant genomic instability leading to cell death or tumorigenesis. Mechanistically, telomere fusions require either the classical non-homologous end-joining (C-NHEJ) pathway dependent on Ku70/80 and LIG4, or the alternative non-homologous end-joining (A-NHEJ), which relies on PARP1 and LIG3. Here, we show that the tumour suppressor BRCA1, together with its interacting partner CtIP, both acting in end resection, also promotes end-joining of uncapped telomeres. BRCA1 and CtIP do not function in the ATM-dependent telomere damage signalling, nor in telomere overhang removal, which are critical for telomere fusions by C-NHEJ. Instead, BRCA1 and CtIP act in the same pathway as LIG3 to promote joining of de-protected telomeres by A-NHEJ. Our work therefore ascribes novel roles for BRCA1 and CtIP in end-processing and fusion reactions at uncapped telomeres, underlining the complexity of DNA repair pathways that act at chromosome ends lacking protective structures. Moreover, A-NHEJ provides a mechanism of previously unanticipated significance in telomere dysfunction-induced genome instability.
Highlights
Telomeres are structures at the ends of linear chromosomes, which consist of long stretches of repetitive double-stranded DNA ending in a 30 single-stranded overhang
The same mouse embryonic fibroblasts (MEFs) were separately transduced with CtIP, MRE11 and NBS1 short hairpin RNA (shRNA), each in combination with TRF2 shRNA, and the reduction in protein levels was monitored by Western blotting
Consistent with ligase 4 (LIG4)-dependent canonical NHEJ being the primary mechanism for uncapped telomere ligation, we found that fusions elicited by TRF2 removal in Lig4À/À MEFs (Fig 3C) were lowered to approximately 7.6% compared to LIG4-proficient cells (Fig 3D)
Summary
Telomeres are structures at the ends of linear chromosomes, which consist of long stretches of repetitive double-stranded DNA ending in a 30 single-stranded overhang. The shelterin component TRF2 plays a key role in telomere protection and prevents ATM-dependent DNA damage signalling at telomeres. The DDR emanating from uncapped telomeres leads to irreversible cell cycle arrest or cell death, limiting the proliferative potential of cells harbouring potentially deleterious mutations. This phenotype is similar to the state arising during physiological ageing and senescence due to erosion of telomeric repeats. Telomeric DDR activates downstream cell cycle effectors, which engage the DNA repair machinery to join unprotected telomeres into aberrant chromosomal end-to-end fusions that drive genomic instability and oncogenic transformation (Maser & DePinho, 2004)
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