LARP7 is a BRCA1 ubiquitinase substrate and regulates genome stability and tumorigenesis

Zhang, F.; Yan, P.; Yu, H.; Le, H.; li, Z.; Chen, J.; Liang, X.; Wang, S.; Wei, W.; Liu, L.; Zhang, Y.; Ji, X.; Xie, A.; Chen, W.; Han, Z.; Pu, W. T.; Chen, S.; Chen, Y.; Sun, K.; Ge, B.; zhang, B.

doi:10.1101/808535

bioRxiv · 10.1101/808535

LARP7 is a BRCA1 ubiquitinase substrate and regulates genome stability and tumorigenesis

Zhang, F.·Yan, P.·Yu, H.·Le, H.·li, Z.·Chen, J.·Liang, X.·Wang, S.·Wei, W.·Liu, L.·Zhang, Y.·Ji, X.·Xie, A.·Chen, W.·Han, Z.·Pu, W. T.·Chen, S.·Chen, Y.·Sun, K.·Ge, B.·zhang, B.

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Abstract

Attenuated DNA repair leads to genomic instability and tumorigenesis. BRCA1/BARD1 are the best known tumor suppressors that promote homology recombination (HR) and arrest cell cycle at G2/M checkpoint. As E3 ubiquitin ligases, their ubiquitinase activity has been known to involve in the HR and tumor suppression, but the mechanism remains ambiguous. Here, we demonstrated upon genotoxic stress, BRCA1 together with BARD1 catalyzed the K48 ployubiquitination on LARP7, a 7SK RNA binding protein known to control RNAPII pausing, and thereby degraded it through 26S ubiquitin-proteasome pathway. Depleting LARP7 suppressed the expression of CDK1 complex, arrested cell at G2/M DNA damage checkpoint and reduced BRCA2 phosphorylation which thereby facilitated RAD51 recruitment to damaged DNA to enhance HR. Importantly, LARP7 depletion observed in breast patients lead to the chemoradiotherapy resistance both in vitro and in vivo. Together, this study unveils a mechanism by which BRCA1/BARD1 utilizes their E3 ligase activity to control HR and cell cycle, and highlights LARP7 as a potential target for cancer prevention and therapy.\n\nHighlightsO_LIDNA damage response downregulates LARP7 through BRCA1/BARD1\nC_LIO_LIBRCA1/BARD1 catalyzes the K48 polyubiquitination on LARP7\nC_LIO_LILARP7 promotes G2/M cell cycle transition and tumorigenesis via CDK1 complex\nC_LIO_LILARP7 disputes homology-directed repair that leads to tumor therapy resistance\nC_LI

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Zhang, F., Yan, P., Yu, H., Le, H., li, Z., Chen, J., Liang, X., Wang, S., Wei, W., Liu, L., Zhang, Y., Ji, X., Xie, A., Chen, W., Han, Z., Pu, W. T., Chen, S., Chen, Y., Sun, K., Ge, B., zhang, B.. 2019-10-17. LARP7 is a BRCA1 ubiquitinase substrate and regulates genome stability and tumorigenesis. https://doi.org/10.1101/808535

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