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

Cell Death and Differentiation
Jiyuan ChenLin-Yu Lu

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.

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Citations

Sep 19, 2020·Molecular & Cellular Oncology·J J Krais, N Johnson
Dec 10, 2020·International Journal of Molecular Sciences·Xunwen XueNing-Ang Liu
Feb 12, 2021·Bioorganic & Medicinal Chemistry·Yanli SunShijie Chen
May 1, 2021·Cancers·Gabriel Matos-RodriguesBernard S Lopez
Jul 30, 2021·Nature·Jordan R BeckerJ Ross Chapman

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Methods Mentioned

BETA
chromosomal aberrations
chromosomal aberration
flow cytometry
transfection

Software Mentioned

BWA
Picard Toolkit
mem
SvABA
Picard
GATK
Circos
samtools
SvAVA

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