The pro-autophagic protein AMBRA1 coordinates cell cycle progression by regulating CCND (cyclin D) stability

The scaffold protein AMBRA1 regulates the early steps of autophagosome\r\nformation and cell growth, and its deficiency is associated with\r\nneurodevelopmental defects and cancer. In a recent study, we show that\r\nAMBRA1 is a key factor in the upstream branch of the MYCN-MYC and\r\nCDK4-CDK6-dependent regulation of G1/S phase transition. Indeed, in the\r\ndeveloping neuroepithelium, in neural stem cells, and in cancer cells,\r\nwe demonstrate that AMBRA1 regulates the expression of D-type cyclins by\r\ncontrolling both their proteasomal degradation and their\r\nMYCN-MYC-mediated transcription. Also, we show that this regulation axis\r\nmaintains genome integrity during DNA replication, and we identify a\r\npossible line of treatment for tumors downregulating AMBRA1 and/or\r\noverexpressing CCND1 (cyclin D1), by demonstrating that AMBRA1-depleted\r\ncells carry an AMBRA1-loss-specific lethal sensitivity to CHEK1\r\ninhibition. Interestingly, we show that this aspect is specific for\r\nAMBRA1 loss, because ATG7 knockdown does not display the same response\r\nto CHEK1 inhibitors. Hence, our findings underscore that the\r\nAMBRA1-CCND1 pathway represents a novel crucial mechanism of cell cycle\r\nregulation, deeply interconnected with genomic stability in development\r\nand cancer.