| Induced pluripotency is a genetic reprogramming technique in which adult somatic cells, such as skin fibroblasts or blood lymphocytes, are reprogrammed back to a primordial state functionally identical to embryonic stem cells (ESCs). This is accomplished using forced expression of the stem cell genes Oct3/4, Sox2, Klf4 and c-Myc, collectively referred to as the Yamanaka factors. Although the resulting induced pluripotent stem cells (iPSCs) are donor-autologous and therefore overcome the obstacles that have prevented widespread medical use of ESCs, our understanding of the mechanisms of induced pluripotency remains limited. I identified a previously unknown role for the DNA repair protein Poly (ADP-Ribose) Polymerase 1 (PARP-1) as being critical for induced pluripotency to occur. Fibroblasts deficient in this gene fail to reprogram or give rise to iPSCs, as do cells that have been treated with a PARP-1 chemical inhibitor. This same inhibitor also causes ESCs and iPSCs to lose their pluripotency. Molecular studies identify Sox2 as a mechanism by which PARP-1 regulates pluripotency, and that PARylation of Sox2 is required to maintain normal Sox2 levels. Lastly, inclusion of PARP-1 as a fifth factor supplementing the Yamanaka reprogramming repertoire results in significant enhancement in reprogramming somatic cells. Together, these findings describe a new role for PARP-1 as a master facilitator of pluripotency. |
