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Abstract The TGFβ and Ras-MAPK pathways play critical roles in cell development and cell cycle regulation, as well as in tumor formation and metastasis. In the absence of cellular transformation, these pathways operate in opposition to one another, where TGFβ maintains an undifferentiated cell state and suppresses proliferation, while Ras-MAPK pathways promote proliferation, survival and differentiation. However, in colorectal and pancreatic cancers, the opposing pathways' mechanisms are simultaneously activated in order to promote cancer progression and metastasis. Here, we highlight the roles of the TGFβ and Ras-MAPK pathways in normal and malignant states, and provide an explanation for how the concomitant activation of these pathways drives tumor biology. Finally, we survey potential therapeutic targets in these pathways.

The tumour suppressor complex BRCA1BARD1 functions in the repair of DNA double-stranded breaks by homologous recombination. During this process, BRCA1BARD1 facilitates the nucleolytic resection of DNA ends to generate a single-stranded template for the recruitment of another tumour suppressor complex, BRCA2PALB2, and the recombinase RAD51. Here, by examining purified wild-type and mutant BRCA1BARD1, we show that both BRCA1 and BARD1 bind DNA and interact with RAD51, and that BRCA1BARD1 enhances the recombinase activity of RAD51. Mechanistically, BRCA1BARD1 promotes the assembly of the synaptic complex, an essential intermediate in RAD51-mediated DNA joint formation. We provide evidence that BRCA1 and BARD1 are indispensable for RAD51 stimulation. Notably, BRCA1BARD1 mutants with weakened RAD51 interactions show compromised DNA joint formation and impaired mediation of homologous recombination and DNA repair in cells. Our results identify a late role of BRCA1BARD1 in homologous recombination, an attribute of the tumour suppressor complex that could be targeted in cancer therapy., Author(s): Weixing Zhao (corresponding author) [1]; Justin B. Steinfeld [2]; Fengshan Liang [1, 3, 4]; Xiaoyong Chen [3, 4]; David G. Maranon [5]; Chu Jian Ma [2]; Youngho Kwon [1]; [...]