Eukaryotic DNA damage checkpoint activation in response to double-strand breaks

Abstract

Double-strand breaks (DSBs) are the most detrimental form of DNA damage. Failure to repair these cytotoxic lesions can result in genome rearrangements conducive to the development of many diseases, including cancer. The DNA damage response (DDR) ensures the rapid detection and repair of DSBs in order to maintain genome integrity. Central to the DDR are the DNA damage checkpoints. When activated by DNA damage, these sophisticated surveillance mechanisms induce transient cell cycle arrests, allowing sufficient time for DNA repair. Since the term "checkpoint" was coined over 20 years ago, our understanding of the molecular mechanisms governing the DNA damage checkpoint has advanced significantly. These pathways are highly conserved from yeast to humans. Thus, significant findings in yeast may be extrapolated to vertebrates, greatly facilitating the molecular dissection of these complex regulatory networks. This review focuses on the cellular response to DSBs in Saccharomyces cerevisiae, providing a comprehensive overview of how these signalling pathways function to orchestrate the cellular response to DNA damage and preserve genome stability in eukaryotic cells.

Unrepaired DNA damage facilitates elimination of uniparental chromosomes in interspecific hybrid cells

“…57 Most chromosomal fragments and rearrangements may be caused by faults in DNA damage repair. 58,59 In our results, deficiency in DNA damage repair on human chromosomes occurs after cell fusion (Fig. 4A and B).…”

“…Though DNA damage occurs frequently in normal cells, the DNA damage checkpoint monitors the efficient and accurate repair to maintain genomic stability. 58,60 If the DNA damage remains unrepaired, the cells may enter cellular senescence or programmed cell death. 42,61 However, our results from live cell imaging ( Fig.…”

“…58,63 The NHEJ is the primary DNA repair pathway in somatic cells, especially in G 1 phase. 60 Though NHEJ has been suggested to be error-prone, its efficiency on DNA damage repair is high.…”

Rad51-Dependent Aberrant Chromosome Structures at Telomeres and Ribosomal DNA Activate the Spindle Assembly Checkpoint

“…Rad3 phosphorylates and activates the downstream effecter kinase Chk1. When the DNA damage checkpoint is activated, Chk1 phosphorylates Cdc25 and Wee1, which maintain Cdc2 in an inactive state, resulting in cell cycle arrest at the G 2 /M transition (7)(8)(9)(10). A link between DNA damage and the SAC in many organisms, including Saccharomyces cerevisiae, Schizosaccharomyces pombe, Drosophila, and humans (11)(12)(13)(14)(15)(16)(17)(18), has been suggested.…”

Tipin Functions in the Protection against Topoisomerase I Inhibitor

“…Phosphorylation of Chk1 by the ATR-ATRIP complex activates Chk1, resulting in a delay in cell cycle progression and inhibition of late origin firing (32)(33)(34). Rad17 increases the phosphorylation activity of ATR as a 9-1-1 clamp loader (35,36).…”