Abstract
The astonishing survival abilities of Vicia faba, one the earliest domesticated plants, are associated, among other things, to the highly effective replication stress response system which ensures smooth cell division and proper preservation of genomic information. The most crucial pathway here seems to be the ataxia telangiectasia-mutated kinase (ATM)/ataxia telangiectasia and Rad3-related kinase (ATR)-dependent replication stress response mechanism, also present in humans. In this article, we attempted to take an in-depth look at the dynamics of regeneration from the effects of replication inhibition and cell cycle checkpoint overriding causing premature chromosome condensation (PCC) in terms of DNA damage repair and changes in replication dynamics. We were able to distinguish a unique behavior of replication factors at the very start of the regeneration process in the PCC-induced cells. We extended the experiment and decided to profile the changes in replication on the level of a single replication cluster of heterochromatin (both alone and with regard to its position in the nucleus), including the mathematical profiling of the size, activity and shape. The results obtained during these experiments led us to the conclusion that even “chaotic” events are dealt with in a proper degree of order.
Highlights
Replication stress is a phenomenon which has serious implications for genome duplication, genome division, and genome stability [1]
Failure in resolving cellular replication stress and its consequences usually leads to various diseases, for instance, ciliopathies, cancer, Bloom syndrome, Seckel syndrome, and others, some of which are linked with events such as mitotic catastrophe and/or genome chaos [5,6,7,8]
Cells respond to DNA replication stress by using three partially distinct, but overlapping the intra-S-phase checkpoints, including (i) the replication checkpoint or replication-dependent intra-S-phase checkpoint and (ii) replication-independent intra-S-phase checkpoint or double-strand break (DSB)-induced intra-S-phase checkpoint together with (iii) the replication-dependent S-M checkpoint, are vital for the well-being of the cell as they are responsible for arresting the entry to mitosis in case of incomplete genome replication [9,10,11,12]
Summary
Replication stress is a phenomenon which has serious implications for genome duplication, genome division, and genome stability [1]. Eukaryotic cells have developed ataxia telangiectasiamutated kinase (ATM)- and ataxia telangiectasia and Rad3-related kinase (ATR)-dependent mechanisms that detect and repair this damage [2]; these pathways prevent the cell from entering the mitosis, preventing the division of incomplete and improperly formed chromosomes [3,4] (Supplementary Figure S1). There are several factors that can induce it, they all result in the bypass of the S-M and G2-M ATM/ATR-dependent checkpoints of the cell cycle and cause cells with incomplete DNA duplication to start premature mitotic division (Supplementary Figure S1). PCC induction forces the cell to enter untimely mitosis and to cope with a couple of stressful factors such as (i) the continuation of unfinished replication, (ii) DNA repair and (iii) DNA condensation simultaneously
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