TRF2 (TERF2) binds to telomeric repeats and is critical for telomere integrity. 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(ADPribose) polymerase (PARP)-dependent and requires the N-terminal basic domain. The phase II recruitment requires the C-terminal MYB/ SANT domain and the iDDR region in the hinge domain, which is mediated by the MRE11 complex and is stimulated by TERT. PARPdependent recruitment of intrinsically disordered proteins contributes to transient displacement of TRF2 that separates two phases. TRF2 binds to I-PpoI-induced DNA double-strand break sites, which is enhanced by the presence of complex damage and is dependent on PARP and the MRE11 complex. TRF2 depletion affects non-sister chromatid homologous recombination repair, but not homologous recombination between sister chromatids or non-homologous endjoining pathways. Our results demonstrate a unique recruitment mechanism and function of TRF2 at non-telomeric DNA damage sites.
Summary StatementTRF2 is recruited to damage sites by a two-step mechanism and functions in non-sister chromatid homologous recombination repair 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 nontelomeric 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 Nterminal 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.All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
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