Physiological Roles of DNA Double-Strand Breaks

Abstract

Genomic integrity is constantly threatened by sources of DNA damage, internal and external alike. Among the most cytotoxic lesions is the DNA double-strand break (DSB) which arises from the cleavage of both strands of the double helix. Cells boast a considerable set of defences to both prevent and repair these breaks and drugs which derail these processes represent an important category of anticancer therapeutics. And yet, bizarrely, cells deploy this very machinery for the intentional and calculated disruption of genomic integrity, harnessing potentially destructive DSBs in delicate genetic transactions. Under tight spatiotemporal regulation, DSBs serve as a tool for genetic modification, widely used across cellular biology to generate diverse functionalities, ranging from the fundamental upkeep of DNA replication, transcription, and the chromatin landscape to the diversification of immunity and the germline. Growing evidence points to a role of aberrant DSB physiology in human disease and an understanding of these processes may both inform the design of new therapeutic strategies and reduce off-target effects of existing drugs. Here, we review the wide-ranging roles of physiological DSBs and the emerging network of their multilateral regulation to consider how the cell is able to harness DNA breaks as a critical biochemical tool.

USP52 regulates DNA end resection and chemosensitivity through removing inhibitory ubiquitination from CtIP

“…Double-strand breaks (DSBs) are known to be one of the most lethal types of DNA lesions in mammalian cells 1 , 2 . Exogenous and endogenous DNA damaging agents such as radiation, carcinogens, and replication stress destroy the integrity and stability of genome, and contribute to the pathogenesis of various diseases, including developmental defects, immune deficiency, premature aging, and cancer 1 , 3 – 5 . To eliminate the risk of DSBs, cells have evolved a complex network to sense and repair damaged DNA, collectively known as the DNA damage response (DDR) pathway 5 – 7 .…”

O-Glcnac Glycosylation of Rad51 Plays an Important Role in Promoting Colorectal Cancer Cell Invasion

“…In contrast, researches on the correlation between Rad51 and tumor metastasis are still insufficient. It is well-known that the process of tumor cell invasion and metastasis is also an immune escape process, during which tumor cells in microenvironment escaped the direct attack of immune cells through enhancing DNA damage repair, meanwhile gained the ability against the cytotoxic effects of chemotherapy drugs finally resulting from acquiring some growth advantage [20]. Recently, a study from the Medical Center of Montpellier University in France revealed the key role of DNA repair in the progression of metastatic circulating colon cancer cells [21].…”

Archaeal DNA Repair Mechanisms

“…DSBs can be generated "accidentally" by missteps of information processing machineries, i.e., by mistiming of replication, replication-transcription complex conflicts, and replication or transcription through existing DNA damage/secondary structures [13][14][15][16]. DSBs are also purposefully generated as essential intermediates of many nucleic acid metabolism pathways [17][18][19][20] and if such pathways are aborted prematurely, intermediate complexes may be released inappropriately. Unchecked DSBs can be extremely detrimental to cellular health, causing arrests of replication and transcription which may lead to apoptosis.…”