Abstract
Faithful duplication of the human genome during the S phase of cell cycle and accurate segregation of sister chromatids in mitosis are essential for the maintenance of chromosome stability from one generation of cells to the next. Cells that are copying their DNA in preparation for division can suffer from ‘replication stress’ (RS) due to various external or endogenous impediments that slow or stall replication forks. RS is a major cause of pathologies including cancer, premature ageing and other disorders associated with genomic instability. It particularly affects genomic loci where progression of replication forks is intrinsically slow or problematic, such as common fragile site (CFS), telomeres, and repetitive sequences. Although the eukaryotic cell cycle is conventionally thought of as several separate steps, each of which must be completed before the next one is initiated, it is now accepted that incompletely replicated chromosomal domains generated in S phase upon RS at these genomic loci can result in late DNA synthesis in G2/M. In 2013, during investigations into the mechanism by which the specialized DNA polymerase eta (Pol η) contributes to the replication and stability of CFS, we unveiled that indeed some DNA synthesis was still occurring in early mitosis at these loci. This surprising observation of mitotic DNA synthesis that differs fundamentally from canonical semi-conservative DNA replication in S-phase has been then confirmed, called “MiDAS”and believed to counteract potentially lethal chromosome mis-segregation and non-disjunction. While other contributions in this Special Issue of Cancers focus on the role of RAS52RAD52 during MiDAS, this review emphases on the discovery of MiDAS and its molecular effectors.
Highlights
Faithful duplication of the human genome during the S phase of cell cycle and accurate segregation of sister chromatids in mitosis are essential for the maintenance of chromosome stability from one generation of cells to the
We reported the first observation of this unexpected extremely late DNA synthesis in 2013, during investigations aiming at exploring the mechanism by which the specialized DNA polymerase eta (Pol η) contributes to the replication and stability of chromosomal common fragile sites (CFS) [19]
It is loaded onto mitotic chromatin following replicative stress and RAD52 foci co-localized with FANCD2 twin foci in early mitosis together with replication protein A (RPA) and MUS81, whereas RAD51 and BRCA2 do not and the RAD52-mediated break-induced replication (BIR) was shown to drive MiDAS at the final stages of the cell cycle [39]
Summary
The failure of the RS response increases the opportunity of incompletely replicated loci or unresolved replication intermediates and a fraction of these under-replicated genomic loci have been evidenced to enter into mitosis. The group of Ian Hickson further documented a late replication completion at CFS upon aphidicolin treatment and demonstrated that it happened in early mitosis [22] These authors reasoned that any EdU found in mitotic cells following an EdU pulse of 20 to 30 min was expected to have been incorporated in G2. They observed EdU on metaphase chromosomes, demonstrating that DNA synthesis was occurring in early mitosis They showed that this mitotic DNA synthesis, a process they called MiDAS, corresponded to broken CFS loci by combining EdU detection with fluorescent in situ hybridization (FISH) [22].
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