Cancer Genomics: Restorative Senescence, Transition to Unicellularity, DDR Circuits, and the Status Quo Ante

All non-gametogenic germlines, including those of humans, protists, and cancer, are capable of proliferation through asymmetric cell division (ACD) and stem cell differentiation, and can be classified as NG germlines or CSC-germlines. These cells are evolutionary descendants of the hypoxic Urgermline that evolved from the common ancestor of amoebozoans, metazoans, and fungi, and follow its physiological and molecular characteristics. Modern germlines and stem cells have inherited oxygen sensitivity. Stress, particularly hypoxic-hyperoxic shock, alters their genome, damages homologous recombination (HR) genes, and leads to irreparable DNA DSB, leading to the loss of functions such as stemness potential and ACD capacity. DSB-altered cells follow a pattern of unicellularization and genome repair via non-apoptotic senescence and hyperpolyploidization. Markers such as p16 and p12 characterize the dysfunctional cells. A phase of restorative senescence and unicellularization are prerequisites for cancer, but the loss and recovery of germline genome integrity also occur in unicellular organisms and parasitic amoebae. During unicellularization, human multicellular genes (MGs) are downregulated, while ancient, conserved unicellular germline (UG) genes are upregulated. Restorative senescence is an ancient cell state and genome repair mechanism, part of the cellular DNA damage response that restores dysfunctional germline cells to their “status quo ante“. It reconstitutes the architecture, function, and molecular integrity of the germline genome. The cellular DNA damage repair circuitry includes tetraploidy, restorative senescence and senescence exit, proliferation through defective mitosis and symmetric cell division (DSCD), homotypic cell fusion into hyperpolyploid MGRS/PGCC structures, and genome reconstruction within giant hyperpolyploid nuclei.