Processing DNA lesions during mitosis to prevent genomic instability

Abstract

Failure of cells to process toxic double-strand breaks (DSBs) constitutes a major intrinsic source of genome instability, a hallmark of cancer. In contrast with interphase of the cell cycle, canonical repair pathways in response to DSBs are inactivated in mitosis. Although cell cycle checkpoints prevent transmission of DNA lesions into mitosis under physiological condition, cancer cells frequently display mitotic DNA lesions. In this review, we aim to provide an overview of how mitotic cells process lesions that escape checkpoint surveillance. We outline mechanisms that regulate the mitotic DNA damage response and the different types of lesions that are carried over to mitosis, with a focus on joint DNA molecules arising from under-replication and persistent recombination intermediates, as well as DNA catenanes. Additionally, we discuss the processing pathways that resolve each of these lesions in mitosis. Finally, we address the acute and long-term consequences of unresolved mitotic lesions on cellular fate and genome stability.

The Influence of Edaphic Factors on DNA Damage and Repair in Wild Wheat Triticum dicoccoides Körn. (Poaceae, Triticeae)

“…Another type is non-DDR-associated MiDAS, which is RAD51 -dependent and occurs irrespective of the induction of DNA damage [ 52 ]. The endonucleases MUS81/EME1 and BLM helicase are employed in CFSs and induce MiDAS, which minimizes chromosome aberrations and missegregation in the anaphase [ 51 , 53 ]. It was shown for human and rat kangaroo cells that micro-focused laser-induced DNA damage in mitotic chromosomes undergoes DNA repair synthesis; mitotic DNA-damaged cells enter subsequent interphase, and DNA repair continues in the G1 phase [ 54 , 55 ].…”

Cancer Biology and Therapeutics: Navigating Recent Advances and Charting Future Directions

“…3059 alternative splicing events in 2005 genes are induced in liver cancer cells, contributing to dedifferentiation and genomic instability. 51,56 Evading growth suppressor To drive cell development, growth factor receptors must be activated by their linked proteins. Growth factor receptor activation is often highly modulated, as well as the production and secretion of the proteins that activate them.…”

Improving Localized Radiotherapy for Glioblastoma via Small Molecule Inhibition of KIF11

“…More recent work has elucidated that, unlike the other phases of the cell cycle, DNA breaks that occur in mitosis do not trigger a cell cycle arrest unless the breaks are at telomeres or centromeres [ 20 , 21 , 22 ]. This leads to an overall increased sensitivity to DNA damage in mitosis [ 19 , 23 , 24 ]. The DNA lesions can be marked as damaged in mitosis and repaired in G1, but the increased chromosomal instability caused by mitotic progression in the presence of DNA breaks can also lead to an increase in cell death [ 20 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ].…”

“…This leads to an overall increased sensitivity to DNA damage in mitosis [ 19 , 23 , 24 ]. The DNA lesions can be marked as damaged in mitosis and repaired in G1, but the increased chromosomal instability caused by mitotic progression in the presence of DNA breaks can also lead to an increase in cell death [ 20 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ]. Hence, enriching GBM cells in mitosis prior to radiotherapy could serve to increase the level of tumor cell death.…”