Box A of HMGB1 Producing DNA Gaps: A Remedy for the DNA Protection and Rejuvenation Effects in Age- and DNA Damage-Associated Diseases

Abstract

Rathasapa Patarat53941, Wilunplus Khumsri53942, Sikrit Denariyakoon53943 and Apiwat Mutirangura53944*

The world is becoming an aging society at an unprecedented pace, and the health and socioeconomic burden from age-associated diseases continue to rise. Age-associated conditions are causing physical and functional deterioration toward organs failure. Understanding the aging process is the key to developing therapeutic protocols for many Non-Communicable Diseases (NCDs). Recently, persistent DNA damage has been proposed to drive the human aging process. However, the underlying mechanisms of the DNA damage accumulation in the elderly have not been clearly understood. Our research showed the DNA protective role of the naturally occurring DNA gaps called Youth-associated genome-stabilizing DNA gaps (Youth-DNA-gaps). The reduction of the DNA gaps in the elderly accumulates DNA damage. Box A of HMGB1 protein acts as molecular scissors producing Youth-DNA-gaps. Introducing the Box A expression plasmids into the cell resulted in DNA stabilization and rejuvenation. The role of the DNA gap is to relieve the double helix torsion stress and protected DNA from damage. The accumulation of DNA damage also led to chronic inflammation and cellular senescence, which led to the development of many NCDs, such as Diabetes Mellitus, Alzeimer’s disease, Heart Failure, Chronic Obstructive Pulmonary Disease, radiation insult, and cancer. These Box A-produced DNA gaps can revitalize organ functions, rejuvenate senescent cells, and clear organ fibrosis. Therefore, Box A of HMGB1 protein is a genomic stabilizing molecule that can rejuvenate DNA and may be used as a therapeutic agent to cure various NCDs.