The DNA damage response (DDR) comprises different DNA repair mechanisms that rely on histones and their interacting proteins to access DNA lesions through chromatin remodelling. The linker histone H1 not only promotes the binding of downstream DDR factors, but can also regulate the cellular sensitivity to genotoxic agents, although the mechanisms involved are poorly understood. Now, Jurgen Marteijn and colleagues (Mandemaker et al., 2020) show that the H1 chaperone SET is crucial for the regulation of cell survival upon exposure to DNA-damaging agents. The authors observe that SET-depleted cells display increased resistance and, consequently, lower apoptotic rates during DDR triggered by different agents, such as UV light and ionizing radiation, or oxidative base damage. Moreover, reduced apoptosis does not result from replication impairment or defective DNA repair. Instead, knocking down of SET leads to a reduction in the removal of H1 from chromatin, indicating that the chaperone function of SET towards H1 is important for chromatin remodelling and access to DNA lesions sites. Accordingly, knocking down H1 in SET-depleted cells supresses cell survival and UV-damage resistance. Finally, the authors suggest that SET acts downstream of the tumour suppressor p53 to induce apoptosis upon DNA damage. Hence, this work unveils a new function for SET in cell survival during DDR following exposure to DNA-damaging agents.
SETting the histone landscape for DNA repair
SETting the histone landscape for DNA repair. J Cell Sci 1 May 2020; 133 (9): e0902. doi:
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