A chromatin scaffold links nuclear architecture to the DNA damage response
The genetic material of human cells is vulnerable and frequently experiences damage. To counteract these constantly occurring lesions, cells employ sophisticated molecular pathways that are collectively termed the DNA damage response (DDR). An important means by which the DDR protects the genome from unrepaired damage is by modifying the chromatin around the affected regions. Recent work had already identified the main enzymatic components required to trigger chromatin modifications in response to DNA breakage in a fast and robust manner. In contrast, how non-enzymatic architectural chromatin factors impact on the initiation and subsequent spreading of these modifications remains largely unexplored.
The research team around Professor Jiri Lukas at Novo Nordisk Foundation Center for Protein Research, in collaboration with researchers from the Danish Cancer Society and the University of Southern Denmark, addressed this issue by studying a protein called scaffold attachment factor B1 (SAFB1), a non-enzymatic component of the chromatin and potential mediator of long-range chromatin interactions. Employing high-content microscopy and software-assisted image analysis, the researchers found that the DNA damage induced phosphorylation of the histone variant H2AX was compromised in the absence of SAFB1, suggesting that chromatin organization by proteins like SAFB1 is important to determine the extent of this modification. Interestingly, SAFB1 itself was transiently recruited to the sites of DNA damage and the researchers could identify a PARP inhibitor sensitive process called poly(ADP-ribosyl)ation as the mechanism by which SAFB1 is recruited to the broken DNA. When the research team experimentally prolonged the association of SAFB1 with the damaged chromatin compartment, they observed enhanced phosphorylation of H2AX, thus suggesting that the relocalization of SAFB1 is carefully regulated to promote efficient, but at the same time avoid excessive chromatin transactions when cells encounter genomic lesions.
The findings shed light on the dynamic reorganization of the chromatin architecture in response to DNA damage and provide new insights into the mechanisms that safeguard human genomes. Since these mechanisms are often subverted in cancer, the work contributes to current efforts aimed to guide cancer treatment.
Title: The Chromatin Scaffold Protein SAFB1 Renders Chromatin Permissive for DNA Damage Signaling
Authors: Matthias Altmeyer, Luis Toledo, Thorkell Gudjonsson, Merete Grøfte, Maj-Britt Rask, Claudia Lukas, Vyacheslav Akimov, Blagoy Blagoev, Jiri Bartek, Jiri Lukas