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Rev7 和 53BP1/Crb2 防止 RecQ 解旋酶依赖性的 DNA 双链断裂超切割。

Rev7 and 53BP1/Crb2 prevent RecQ helicase-dependent hyper-resection of DNA double-strand breaks.

机构信息

Department of Cell Biology, Yale School of Medicine, New Haven, United States.

出版信息

Elife. 2018 Apr 26;7:e33402. doi: 10.7554/eLife.33402.

DOI:10.7554/eLife.33402
PMID:29697047
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5945276/
Abstract

Poly(ADP ribose) polymerase inhibitors (PARPi) target cancer cells deficient in homology-directed repair of DNA double-strand breaks (DSBs). In preclinical models, PARPi resistance is tied to altered nucleolytic processing (resection) at the 5' ends of a DSB. For example, loss of either 53BP1 or Rev7/MAD2L2/FANCV derepresses resection to drive PARPi resistance, although the mechanisms are poorly understood. Long-range resection can be catalyzed by two machineries: the exonuclease Exo1, or the combination of a RecQ helicase and Dna2. Here, we develop a single-cell microscopy assay that allows the distinct phases and machineries of resection to be interrogated simultaneously in living cells. Using this assay, we find that the 53BP1 orthologue and Rev7 specifically repress long-range resection through the RecQ helicase-dependent pathway, thereby preventing hyper-resection. These results suggest that 'rewiring' of BRCA1-deficient cells to employ an Exo1-independent hyper-resection pathway is a driver of PARPi resistance.

摘要

聚（ADP-核糖）聚合酶抑制剂（PARPi）针对的是缺乏同源定向修复 DNA 双链断裂（DSBs）的癌细胞。在临床前模型中，PARPi 耐药与 DSB 5'端的改变核酶加工（切除）有关。例如，53BP1 或 Rev7/MAD2L2/FANCV 的缺失会解除对切除的抑制，从而导致 PARPi 耐药，尽管其机制尚不清楚。长距离切除可以由两种机制催化：外切酶 Exo1，或 RecQ 解旋酶和 Dna2 的组合。在这里，我们开发了一种单细胞显微镜检测方法，可以同时在活细胞中检测到切除的不同阶段和机制。使用该检测方法，我们发现 53BP1 同源物和 Rev7 通过 RecQ 解旋酶依赖性途径特异性抑制长距离切除，从而防止过度切除。这些结果表明，BRCA1 缺陷细胞“重新布线”以采用 Exo1 不依赖的过度切除途径是 PARPi 耐药的驱动因素。

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