TRF1 interacts with XRCC4 and XLF at telomeres

Abstract

At telomeres, the shelterin complex is entrusted with a protective role against DNA repair mechanisms that could mistakenly recognize the natural ends of chromosomes as the product of a double strand break, and create telomeric end‐to‐end fusions that can drive genome instability and tumorigenesis. Paradoxically, telomeres also harbor several members of the DNA repair machinery whose actions they are trying to block, like members of the NHEJ pathway. How these NHEJ proteins are prevented from engaging in NHEJ at telomeres is not fully understood. Using protein fragment complementation assay, we have detected novel interactions between shelterin proteins TRF1 and TRF2 with XRCC4 and XLF, two NHEJ proteins that interact and are involved in later steps during DSB repair. Furthermore, cells expressing interacting TRF1 and XRCC4 proteins displayed clear punctate staining that co‐localized with other telomeric proteins, indicating that XRCC4 and TRF1 can interact at telomeres. Mutations that disrupt XRCC4‐XLF interaction or known phosphorylation sites for ATM and DNA‐PKcs kinases did not impair XRCC4‐TRF1 interaction nor did they impair XRCC4 localization at telomeres. Overall our results suggest that NHEJ proteins XRCC4 and XLF can be recruited to telomeres through interactions with shelterin proteins TRF1 and TRF2 in ways that require neither XRCC4‐XLF interaction nor ATM or DNA‐PKcs phosphorylation.