Abstract
Unlike bacteria, mammalian cells need to complete DNA replication before segregating their chromosomes for the maintenance of genome integrity. Thus, cells have evolved efficient pathways to restore stalled and/or collapsed replication forks during S-phase, and when necessary, also to delay cell cycle progression to ensure replication completion. However, strong evidence shows that cells can proceed to mitosis with incompletely replicated DNA when under mild replication stress (RS) conditions. Consequently, the incompletely replicated genomic gaps form, predominantly at common fragile site regions, where the converging fork-like DNA structures accumulate. These branched structures pose a severe threat to the faithful disjunction of chromosomes as they physically interlink the partially duplicated sister chromatids. In this review, we provide an overview discussing how cells respond and deal with the under-replicated DNA structures that escape from the S/G2 surveillance system. We also focus on recent research of a mitotic break-induced replication pathway (also known as mitotic DNA repair synthesis), which has been proposed to operate during prophase in an attempt to finish DNA synthesis at the under-replicated genomic regions. Finally, we discuss recent data on how mild RS may cause chromosome instability and mutations that accelerate cancer genome evolution.
Highlights
Subject Category: Biochemistry, cellular and molecular biology Subject Areas: molecular biology/biochemistry/cellular biology Keywords: replication stress, common fragile sites, mitotic DNA repair synthesis, break-induced replication, ultrafine DNA bridges, chromosome instability
We provide an overview discussing how cells respond and deal with the underreplicated DNA structures that escape from the S/Gap period 2 (G2) surveillance system
We focus on recent research of a mitotic break-induced replication pathway, which has been proposed to operate during prophase in an attempt to finish DNA synthesis at the under-replicated genomic regions
Summary
DNA replication and cell division are crucial for the continuity of life. These two events are tightly coordinated and regulated throughout the cell cycle to ensure faithful transmission of genetic material to every offspring cell. This work shows how S-phase kinases influence the mitosis-promoting factors, and explains why the lack of ATR activity leads to premature mitotic entry despite the presence of ongoing DNA synthesis activity [13]. CDK2-cyclin E/A complex represses Cdc to re-associate with the origins during S-phase, which prevents DNA re-replication This kinase complex promotes ATR-Chk, CDK1 and PLK1 activity. (b) ATR couples S-phase progression with G2/mitotic entry by inhibiting both CDK2 and CDK1 activity (left) This function is critical during replication stress (RS) conditions because cells must ensure full duplication and the genome prior to mitotic entry (right). We will review several new studies that have started to unravel the mechanistic insights of how RS induces chromosome instability (CIN), and how these lead to mitotic faults/defects
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