Histone H1 eviction by the histone chaperone SET reduces cell survival following DNA damage.

Many chromatin remodeling and modifying proteins are involved in the DNA damage response by stimulating repair or inducing DNA damage signaling. Interestingly, here we identified that down regulation of the H1-interacting protein SET results in increased resistance to a wide variety of DNA damaging agents. We found that this increased resistance is not the result of an inhibitory effect of SET on DNA repair, but rather the consequence of a suppressed apoptotic response to DNA damage. We further provide evidence that the histone chaperone SET is responsible for the eviction of H1 from chromatin. Knock down of H1 in SET-depleted cells resulted in re-sensitization of cells to DNA damage, suggesting that the increased DNA damage resistance in SET-depleted cells is the result of enhanced retention of H1 on chromatin. Finally, clonogenic survival assays show that SET and p53 are epistatic in attenuating DNA damage-induced cell death. Altogether, our data show a role for SET in the DNA damage response as a regulator of cell survival following genotoxic stress.