The linker histone chaperone Prothymosin α (PTMA) is essential for efficient DNA damage repair and the recruitment of...

Mammalian cells have numerous DNA repair pathways to repair lesions generated by replication errors, metabolism, and exogenous agents. Cells can sense and respond to DNA damage within seconds, suggesting that there is a highly effective sensor of lesions although the mechanistic details are unclear. The DNA damage response in mammalian cells results in a localized transient de-condensation of chromatin, loss of linker histones and the recruitment of DNA repair proteins such as PARP1 and chromatin remodelers.

Here we investigated the interactions between poly(ADP-ribose) polymerase-1 (PARP1), the linker histone H1.0 and linker histone chaperone Prothymosin α (PTMA). Using H1.0 tagged with a photoconvertible fluorescent protein, we observed a significant increase in the initial rate of exit of H1.0 from regions of chromatin containing microirradiation-induced DNA lesions. Surprisingly, this was also seen in Parp1^-/- cells but not in stable cell lines with homozygous null mutations in the PTMA gene (Ptma^-/-). The recruitment of PARP1 to damaged DNA was inhibited by overexpression of a mutant of H1.0 with a tighter chromatin-binding affinity or by reduced expression of PTMA. Relative to the wild type, Ptma^-/- cell lines displayed increased sensitivity to DNA-damaging agents.

We suggest that DNA damage alters the interaction of H1.0 with the nucleosome to allow the chaperone PTMA to bind and promote release of linker histones thereby initiating the local chromatin de-condensation necessary for the efficient recruitment of repair proteins such as PARP1. In this context linker histones may serve as in situ "sensors" of DNA damage.