Department of Neurosurgery and The Brain Tumor Center, University of California-San Francisco, San Francisco, CA 94158, USA.
Core Diagnostics, 3535 Breakwater Avenue, Hayward, CA 94545, USA.
Sci Transl Med. 2021 May 5;13(592). doi: 10.1126/scitranslmed.abc7211.
About 10% of all tumors, including most lower-grade astrocytoma, rely on the alternative lengthening of telomere (ALT) mechanism to resolve telomeric shortening and avoid limitations on their growth. Here, we found that dependence on the ALT mechanism made cells hypersensitive to a subset of poly(ADP-ribose) polymerase inhibitors (PARPi). We found that this hypersensitivity was not associated with PARPi-created genomic DNA damage as in most PARPi-sensitive populations but rather with PARPi-induced telomere fusion. Mechanistically, we determined that PARP1 was recruited to the telomeres of ALT-dependent cells as part of a DNA damage response. By recruiting MRE11 and BRCC3 to stabilize TRF2 at the ends of telomeres, PARP1 blocked chromosomal fusion. Exposure of ALT-dependent tumor cells to a subset of PARPi induced a conformational change in PARP1 that limited binding to MRE11 and BRCC3 and delayed release of the TRF2-mediated block on lethal telomeric fusion. These results therefore provide a basis for PARPi treatment of ALT-dependent tumors, as well as establish chromosome fusion as a biomarker of their activity.
约 10%的肿瘤，包括大多数低级别星形细胞瘤，依赖端粒的非经典延长（ALT）机制来解决端粒缩短问题，并避免其生长受到限制。在这里，我们发现对 ALT 机制的依赖使细胞对聚（ADP-核糖）聚合酶抑制剂（PARPi）的亚类敏感。我们发现，这种敏感性与大多数 PARPi 敏感群体中 PARPi 引起的基因组 DNA 损伤无关，而是与 PARPi 诱导的端粒融合有关。在机制上，我们确定 PARP1 作为 DNA 损伤反应的一部分被募集到 ALT 依赖性细胞的端粒上。通过招募 MRE11 和 BRCC3 来稳定端粒末端的 TRF2，PARP1 阻止了染色体融合。暴露于 PARPi 的亚类的 ALT 依赖性肿瘤细胞会诱导 PARP1 构象发生变化，从而限制与 MRE11 和 BRCC3 的结合，并延迟释放 TRF2 介导的对致命端粒融合的阻断。因此，这些结果为 PARPi 治疗 ALT 依赖性肿瘤提供了依据，并将染色体融合确立为其活性的生物标志物。
