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53BP1 缺失挽救了 BRCA1 完全敲除小鼠的胚胎致死性，但不能挽救其基因组不稳定性。

53BP1 loss rescues embryonic lethality but not genomic instability of BRCA1 total knockout mice.

机构信息

Key Laboratory of Reproductive Genetics (Ministry of Education) and Women's Reproductive Health Laboratory of Zhejiang Province, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.

出版信息

Cell Death Differ. 2020 Sep;27(9):2552-2567. doi: 10.1038/s41418-020-0521-4. Epub 2020 Mar 5.

DOI:10.1038/s41418-020-0521-4
PMID:32139898
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7429965/
Abstract

BRCA1 is critical for DNA double-strand break (DSB) repair by homologous recombination (HR). BRCA1 deficient mice are embryonic lethal. Previous studies have shown that 53BP1 knockout (KO) rescues embryonic lethality of BRCA1 hypomorphic mutant mice by restoring HR. Here, we show that 53BP1 KO can partially rescue embryonic lethality of BRCA1 total KO mice, but HR is not restored in BRCA1-53BP1 double knockout (DKO) mice. As a result, BRCA1-53BP1 DKO cells are extremely sensitive to PARP inhibitors (PARPi). In addition to HR deficiency, BRCA1-53BP1 DKO cells have elevated microhomology-mediated end joining (MMEJ) activity and G2/M cell cycle checkpoint defects, causing severe genomic instability in these cells. Interestingly, BRCA1-53BP1 DKO mice rapidly develop thymic lymphoma that is 100% penetrant, which is not observed in any BRCA1 mutant mice rescued by 53BP1 KO. Taken together, our study reveals that 53BP1 KO can partially rescue embryonic lethality caused by complete BRCA1 loss without rescuing HR-related defects. This finding suggests that loss of 53BP1 can support the development of cancers with silenced BRCA1 expression without causing PARPi resistance.

摘要

BRCA1 对于同源重组（HR）介导的 DNA 双链断裂（DSB）修复至关重要。BRCA1 缺陷型小鼠是胚胎致死的。先前的研究表明，53BP1 敲除（KO）通过恢复 HR 挽救了 BRCA1 功能不全突变型小鼠的胚胎致死性。在这里，我们发现 53BP1 KO 可以部分挽救 BRCA1 完全 KO 小鼠的胚胎致死性，但 BRCA1-53BP1 双敲除（DKO）小鼠中的 HR 并未恢复。结果，BRCA1-53BP1 DKO 细胞对 PARP 抑制剂（PARPi）极其敏感。除了 HR 缺陷外，BRCA1-53BP1 DKO 细胞还具有升高的微同源介导的末端连接（MMEJ）活性和 G2/M 细胞周期检查点缺陷，导致这些细胞中严重的基因组不稳定性。有趣的是，BRCA1-53BP1 DKO 小鼠迅速发展为胸腺淋巴瘤，其发生率为 100%，而在任何由 53BP1 KO 挽救的 BRCA1 突变型小鼠中均未观察到这种情况。总之，我们的研究揭示了 53BP1 KO 可以部分挽救完全 BRCA1 缺失引起的胚胎致死性，而不会挽救与 HR 相关的缺陷。这一发现表明，53BP1 的缺失可以支持沉默 BRCA1 表达的癌症的发展，而不会引起 PARPi 耐药性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e40a/7429965/92e9517fdf8d/41418_2020_521_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e40a/7429965/96b59e787eb3/41418_2020_521_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e40a/7429965/da650fe8a86d/41418_2020_521_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e40a/7429965/ce38d3fbef09/41418_2020_521_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e40a/7429965/4020d1732b1a/41418_2020_521_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e40a/7429965/5e87ff0b8eb7/41418_2020_521_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e40a/7429965/c8e7ef5d3a03/41418_2020_521_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e40a/7429965/c46ba3a6ad71/41418_2020_521_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e40a/7429965/92e9517fdf8d/41418_2020_521_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e40a/7429965/96b59e787eb3/41418_2020_521_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e40a/7429965/da650fe8a86d/41418_2020_521_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e40a/7429965/ce38d3fbef09/41418_2020_521_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e40a/7429965/4020d1732b1a/41418_2020_521_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e40a/7429965/5e87ff0b8eb7/41418_2020_521_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e40a/7429965/c8e7ef5d3a03/41418_2020_521_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e40a/7429965/c46ba3a6ad71/41418_2020_521_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e40a/7429965/92e9517fdf8d/41418_2020_521_Fig8_HTML.jpg

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