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.
Highlights
Cells in our body constantly encounter all kinds of DNA damage that are repaired by different DNA damage repair pathways
Consistent with previous observations that BRCA1 forms a heterodimer with BARD1 and is required for its stability [18, 19], a dramatic reduction of BARD1 protein level was observed in Brca1Δ5–13/Δ5–13;Trp53bp1−/− mouse embryonic fibroblasts (MEFs) (Fig. 1c)
We have demonstrated that 53BP1 KO can partially rescue embryonic lethality of BRCA1 total KO mice that are homozygous for a bona fide Brca1 null allele
Summary
Cells in our body constantly encounter all kinds of DNA damage that are repaired by different DNA damage repair pathways. The identification of BRCA1’s function in DSB repair pathway choice originates from the finding that 53BP1 KO can fully rescue the embryonic lethality of Brca1Δ11/Δ11 and Brca1Δ2/Δ2 mice [12,13,14,15]. The HR deficiency and genomic instability are fully rescued so that both Brca1Δ11/Δ11; Trp53bp1−/− mice and Brca1Δ2/Δ2;Trp53bp1−/− mice have normal life span and no elevated tumor incidences than wild-type (WT) mice [12,13,14,15] Both Brca1Δ11/Δ11 and Brca1Δ2/Δ2 mice are Brca hypomorphic mutant but not total KO mice. It is still possible that BRCA1 is not completely absent in Brca1ΔC/ΔC mice, in which the truncated BRCA1ΔC proteins might express at low levels and contribute to the viability of Brca1ΔC/ΔC;Trp53bp1−/− mice It remains to be studied if 53BP1 KO can rescue the lethality of bona fide BRCA1 total KO mice. This study reveals that HR deficiency is compatible with embryonic development, but HR is important for preventing tumorigenesis in adults
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