Abstract
TRF2 is a shelterin component critical for telomere integrity. While TRF2 directly recognizes and binds telomeric repeats, evidence suggests that it also localizes to non-telomeric DNA damage sites. However, this recruitment appears to be precarious and functionally controversial. We find that TRF2 recruitment to damage sites occurs by a two-step mechanism: the initial rapid recruitment (phase I) and stable and prolonged association with damage sites (phase II). Phase I is poly(ADP-ribose) polymerase (PARP)-dependent and requires positively charged amino acid residues in the N-terminal domain. The phase II recruitment is through the C-terminal MYB/SANT domain and requires the iDDR region in the hinge domain of TRF2. Phase II is mediated by the MRE11 complex and is stimulated by hTERT. PARP-dependent recruitment of intrinsically disordered proteins contributes to transient displacement of TRF2 that separates phases I and II. TRF2 depletion specifically affects non-sister chromatid homologous recombination (HR) repair, but not HR between sister chromatids or classic and alternative non-homologous endjoining. Our results demonstrate a unique recruitment mechanism and function of TRF2 at non-telomeric DNA damage sites.
Summary Statement TRF2 is recruited to damage sites by a two-step mechanism and functions in non-sister chromatid homologous recombination repair