Ubiquitin's code: UPS orchestrating DNA repair and genomic stability under genotoxic stress

The genetic blueprint of life faces ongoing threats from physical and chemical agents that can disrupt DNA and lead to genomic instability, which is one of the hallmarks of cancer. These agents include external factors like ionizing radiation, UV radiation, radiotherapy, and chemotherapeutic drugs or internal factors like redox imbalance arising from deregulated cellular metabolism. These agents damage DNA by generating inter-strand crosslinks, DNA-protein crosslinks, bulky adducts or double-strand breaks that ultimately decreases genomic integrity and leads to tumorigenesis. The coordinated actions of E3 ubiquitin ligases and deubiquitinases (DUBs) are essential in the precise control of these DNA damage tolerance and repair pathways. This has unravelled vulnerable points for intervention in cancer chemoresistance, since it has been observed that these ubiquitinases and deubiquitinases may upregulate repair proteins that reverses DNA damage conferred by conventional chemotherapeutics. This review focusses on the intricate dynamics of ubiquitination and deubiquitination in controlling DNA damage repair pathways and safeguarding genomic integrity.