About 10–15% of human cancers maintain their telomere length through a homologous-recombination-based process called alternative lengthening of telomeres (ALT). Understanding the mechanism that regulates ALT activity, therefore, is crucial for the design of druggable targets for the often aggressive ALT-linked cancers. TRF1, a duplex telomeric DNA-binding protein and a component of the shelterin complex, which is essential for telomere maintenance, has a key role in the regulation of ALT activity, but how TRF1 effects this regulation is poorly understood. Xu-Dong Zhu and colleagues (p. ) now demonstrate that Cdk1 phosphorylates TRF1 on T371, thereby creating a stable pool of TRF1 that is referred to as (pT371)TRF1. They show that (pT371)TRF1 is a component of ALT-associated PML bodies (APBs), and is required to support APB formation and C-circle production, which are both key features of ALT activity. Next, the authors show that ATM and the homologous-recombination-promoting factors Mre11 and BRCA1 mediate the association of (pT371)TRF1 with APBs, as does transcription-associated DNA damage at telomeres. In addition, the Zhu and colleagues demonstrate that the association of (pT371)TRF1 with APBs is sensitive to RNaseH1 in the presence of the topoisomerase I inhibitor camptothecin that prevents topoisomerase I from resolving RNA–DNA hybrids. The authors therefore propose a model in which transcription-associated DNA damage, perhaps arising from the processing of RNA–DNA hybrids at telomeres, triggers (pT371)TRF1 recruitment to APBs to facilitate ALT activity. This paper provides much-needed insights into the function of (pT371)TRF1 within ALT cells.
