Department of Pharmacology and Chemical Biology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Pharmacology and Chemical Biology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.
DNA Repair (Amst). 2022 Jul;115:103342. doi: 10.1016/j.dnarep.2022.103342. Epub 2022 May 13.
Activation of a telomere maintenance mechanism is key to achieving replicative immortality. Alternative Lengthening of Telomeres (ALT) is a telomerase-independent pathway that hijacks the homologous recombination pathways to elongate telomeres. Commitment to ALT is often associated with several hallmarks including long telomeres of heterogenous lengths, mutations in histone H3.3 or the ATRX/DAXX histone chaperone complex, and incorporation of non-canonical telomere sequences. The consequences of these genetic and epigenetic changes include enhanced replication stress and the presence of transcriptionally permissive chromatin, which can result in replication-associated DNA damage. Here, we detail the molecular mechanisms that are critical to repairing DNA damage at ALT telomeres, including the BLM Helicase, which acts at several steps in the ALT process. Furthermore, we discuss the emerging findings related to the telomere-associated RNA, TERRA, and its roles in maintaining telomeric integrity. Finally, we review new evidence for therapeutic interventions for ALT-positive cancers which are rooted in understanding the molecular underpinnings of this process.
端粒维持机制的激活是实现复制性永生的关键。端粒的非酶延长（ALT）是一种非端粒酶依赖的途径，它劫持同源重组途径来延长端粒。ALT 的承诺通常与几个标志相关联，包括异质长度的长端粒、组蛋白 H3.3 或 ATRX/DAXX 组蛋白伴侣复合物的突变，以及非规范端粒序列的掺入。这些遗传和表观遗传变化的后果包括增强的复制应激和转录允许染色质的存在，这可能导致与复制相关的 DNA 损伤。在这里，我们详细介绍了在 ALT 端粒处修复 DNA 损伤至关重要的分子机制，包括 BLM 解旋酶，它在 ALT 过程的几个步骤中起作用。此外，我们讨论了与端粒相关的 RNA（TERRA）及其在维持端粒完整性中的作用的新发现。最后，我们回顾了针对 ALT 阳性癌症的治疗干预措施的新证据，这些证据源于对这一过程分子基础的理解。
