What is the first step in the intrinsic pathway of apoptosis following DNA damage?

The first step in the intrinsic pathway of apoptosis, particularly in response to DNA damage, is the activation of the p53 protein. P53 is a crucial tumor suppressor that monitors cellular stress, including DNA damage. When DNA damage occurs, p53 becomes stabilized and activated, leading to several important outcomes.

One of the key roles of activated p53 is to initiate the expression of pro-apoptotic factors that promote apoptosis. This includes the upregulation of genes that encode BAX and BAK, which are pro-apoptotic members of the Bcl-2 family. These proteins then contribute to mitochondrial outer membrane permeabilization, resulting in the release of cytochrome c into the cytosol, which ultimately activates the caspase cascade leading to cell death.

Thus, the correct choice reflects the critical moment when p53 acts as a decision-maker in determining whether a cell will repair itself or undergo programmed cell death in response to significant stress like DNA damage.