High mobility group proteins (HMGs) are the most abundant nuclear proteins next to histones and are robustly expressed across tissues and organs. HMGs can uniquely bend or bind distorted DNA, and are central to such processes as transcription, recombination, and DNA repair. However, their dynamic association with chromatin renders capturing HMGs on chromosomes challenging. Recent work has changed this and now implicates these factors in spatial genome organization. Here, I revisit older and review recent literature to describe how HMGs rewire spatial chromatin interactions to sustain homeostasis or promote cellular aging. I propose a 'rheostat' model to explain how HMG-box proteins (HMGBs), and to some extent HMG A proteins (HMGAs), may control cellular aging and, likely, cancer progression.
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Declaration of interests The author has no competing interests to declare.
