The Intra- and Extra-Telomeric Role of TRF2 in the DNA Damage Response

Abstract

Telomere repeat binding factor 2 (TRF2) has a well-known function at the telomeres, which acts to protect the telomere end from being recognized as a DNA break or from unwanted recombination. This protection mechanism prevents DNA instability from mutation and subsequent severe diseases caused by the changes in DNA, such as cancer. Since TRF2 actively inhibits the DNA damage response factors from recognizing the telomere end as a DNA break, many more studies have also shown its interactions outside of the telomeres. However, very little has been discovered on the mechanisms involved in these interactions. This review aims to discuss the known function of TRF2 and its interaction with the DNA damage response (DDR) factors at both telomeric and non-telomeric regions. In this review, we will summarize recent progress and findings on the interactions between TRF2 and DDR factors at telomeres and outside of telomeres.

The shelterin component TRF2 mediates columnar stacking of human telomeric chromatin

“…Unspecific binding of TRF2 to non-telomeric regions may not be surprising given that TRF2 has been shown to bind to other sequences (e.g. with G-quadruplex motifs) to functionally regulate the expression of several genes through epigenetic modification on the promoter (Imran et al, 2021 ; Mukherjee et al, 2019 ). TRF2 also plays a role in neuronal gene silencing, stem cell fate and cancer cell survival through its interaction with repressor element 1-silencing transcription factor (REST), though direct interaction with DNA has not been implicated, we speculate that the ability of TRF2 to bind non-telomeric sequences plays a role in this (Kwon et al, 2013 ; Zhang et al, 2008 ).…”

“…In addition to its specific functions at the telomeres, TRF2 performs various roles in other parts of chromatin (Baker et al, 2011 ; Imran et al, 2021 ; Mukherjee et al, 2019 ). Our study confirms that TRF2 ΔN dimers bind both telomeric and non-telomeric nucleosome arrays.…”

Thioredoxin (Trx): A redox target and modulator of cellular senescence and aging-related diseases

“…TRF2 forms t-loop structures that provide protection for telomeres from the DNA damage response and hinders the activation of ATM and NHEJ pathways, which can lead to telomere fusion and chromosomal instability [ 91 , 111 , 112 ]. By reducing its interaction with MDM2, an E3 ubiquitin ligase, Trx inhibits the ubiquitination and degradation of TRF2 [ 113 , 114 ]. Consequently, Trx may function as a positive regulator of both TRF2 and telomere maintenance, thereby exhibiting potential anti-aging effects.…”

Telomeric-Like Repeats Flanked by Sequences Retrotranscribed from the Telomerase RNA Inserted at DNA Double-Strand Break Sites during Vertebrate Genome Evolution

“…Altogether, these findings strongly suggest that TERC-ITSs were inserted during the repair of break sites in the course of evolution through reverse transcription of TERC sequences and the telomeric repeat array. It is worth mentioning that many DNA repair proteins also interact with telomeres and that, in turn, telomere binding factors can also be recruited at internal chromosomal loci and at DNA double-strand break sites [50][51][52][53][54]. In particular, it has been shown that Ku, a key player in the non-homologous end-joining DNA repair pathway with an affinity for double-strand ends, is also able to bind to the scaRNA domain of TERC [52,55].…”