TERF2-XPF: Caught in the middle; beginnings from the end

Two recent articles suggest new roles for the TERF2-XPF complex (a.k.a. TRF2-XPF)1 in the recognition/repair of DNA damage at non-telomeric chromosomal locations (i.e. “Caught in the Middle”). These new roles for proteins typically ascribed functions at the ends of chromosomes are proposed to be very early events of DNA damage response (i.e. Beginnings from the End). Our previous understanding of a role for the TERF2-XPF complex in the maintenance of chromosome stability included the preservation of telomere length by “suppression” of the recognition of chromosome ends as breaks. One recent paper demonstrates that TERF2 also functions at non-telomeric sites of DNA damage, and does so prior to initiation of the ATM signaling cascade. A second paper goes on to demonstrate that overexpression of TERF2 produces mouse phenotypes similar to those associated with xeroderma pigmentosum, such as cellular hypersensitivity to UV radiation and DNA crosslinking agents, and telomere shortening and chromosome instability in response to DNA damage. Moreover, data are presented illustrating that these abnormal responses are not seen in an XPF−/− background, consistent with a dependency on XPF. Interestingly, both manuscripts focus on events that transpire in response to exogenous DNA damage. Here, we review these exciting findings that suggest new roles for the TERF2-XPF complex and point out several questions that remain to be addressed.