Graphical Abstract Highlights d EMI1 assembles an SCF ubiquitin ligase that constitutively targets RAD51 for degradation d In response to genotoxic stress, CHK1 counteracts EMI1dependent degradation of RAD51 d A subset of TNBC cells develop resistance to PARPi by downregulating EMI1 d Reconstitution of EMI1 expression reestablishes PARPi sensitivity in vitro and in vivo In Brief Marzio et al. report that cellular levels of RAD51 are kept in check by EMI1mediated degradation. Upon DNA damage, CHK1 phosphorylation of RAD51 on Thr309 counteracts this event, allowing RAD51 accumulation and HRR. Downregulation of EMI1 in BRCA1deficient breast cancer cells induces primary and acquired resistance to PARPi both in vitro and in vivo. SUMMARYThe BRCA1-BRCA2-RAD51 axis is essential for homologous recombination repair (HRR) and is frequently disrupted in breast cancers. PARP inhibitors (PARPis) are used clinically to treat BRCAmutated breast tumors. Using a genetic screen, we identified EMI1 as a modulator of PARPi sensitivity in triple-negative breast cancer (TNBC) cells. This function requires the F-box domain of EMI1, through which EMI1 assembles a canonical SCF ubiquitin ligase complex that constitutively targets RAD51 for degradation. In response to genotoxic stress, CHK1-mediated phosphorylation of RAD51 counteracts EMI1-dependent degradation by enhancing RAD51's affinity for BRCA2, leading to RAD51 accumulation. Inhibition of RAD51 degradation restores HRR in BRCA1-depleted cells. Human breast cancer samples display an inverse correlation between EMI1 and RAD51 protein levels. A subset of BRCA1-deficient TNBC cells develop resistance to PARPi by downregulating EMI1 and restoring RAD51-dependent HRR. Notably, reconstitution of EMI1 expression reestablishes PARPi sensitivity both in cellular systems and in an orthotopic mouse model.

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Autoimmune disease is the leading cause of morbidity among women. For largely unknown reasons, many autoimmune diseases show a striking female bias. Fibrosis is a common feature of female-biased autoimmune diseases. This is exemplified by systemic sclerosis (SSc), a debilitating disease marked by progressive skin hardening and organ damage that affects women at ninefold the rate of men. We previously identified the transcriptional cofactor VGLL3 as an immune regulator enriched in female skin whose targets overlap significantly with genes dysregulated in SSc. We further showed that excess epidermal VGLL3 causes cutaneous and systemic autoimmune disease in mice. However, how VGLL3 promotes autoimmunity in the skin remains entirely unexplored. By combining IP-mass spectrometry, RNA-seq, and ChIP-seq approaches in cell culture and transgenic mice with epidermal VGLL3 overexpression, we have found that VGLL3 binds key factors in the Hippo signaling pathway to modulate both immune genes and established Hippo pathway targets. These targets include the pro-fibrotic factor CTGF and members of the TGF-b pathway, both of which have been implicated in SSc pathogenesis. Consistent with this, transgenic mice with epidermal VGLL3 overexpression show gross and microscopic features of skin fibrosis. These findings elucidate the molecular mechanisms by which VGLL3 promotes autoimmunity and leads to the hallmark fibrosis of many autoimmune diseases such as SSc. Furthermore, this reveals a previously unexplored connection between autoimmune disease and the Hippo signaling pathway, which has recently been linked to organ fibrosis.