Mechanisms Of Replication Stress-induced Non-random Segregation Of Damaged Chromosomes

Cell division is divided into symmetric cell division(SCD)and asymmetric cell division(ACD).The balance between asymmetry and symmetrical mitosis must be precisely controlled over time and space throughout the life cycle.Coordination of asymmetric cell division requires control of a large number of intracellular and extracellular biological processes and signaling networks.Interference with these events leads to dynamic changes in self-renewal and differentiation within the cell population,which is highly correlated with cancer growth and progression.Non-random DNA segregation is a key scientific issue in asymmetric cell division,in which the chromatid carrying the parent's template DNA strand is inherited by only one of the two daughter cells.Although this phenomenon has been observed in several species and cell types,we know very little about the mechanisms and physiological relevance of non-random DNA segregation.Studies have shown that the frequency of asymmetric cell division of muscle stem cells is significantly affected by oxygen tension;In the acute tissue damage of skeletal muscle,non-random DNA segregation in muscle stem cells can also be observed[62];Non-random DNA segregation are described as associated with cell contact,high cell density,hypoxia(1%),and serum deprivation.These evidences suggest that non-random DNA segregation may be regulated by the microenvironment.In addition,successful DNA replication and subsequent uniform segregation during mitosis is critical for genomic stability maintenance.Studies have shown that replication stress is finely regulated by the microenvironment and is critical to the maintenance of genome stability.Therefore,we suspect that replication stress induces differentiation of chromosomal DNA,which in turn affects the non-random DNA segregation.Our team used replication stress-inducing agents such as APH to induce replication stress on human osteosarcoma(U-20S)cells,demonstrating that replication stress can induce non-random DNA segregation.Moreover,oncogene-induced replication stress can also induce non-random DNA segregation,suggesting that non-random DNA segregation is associated with cancer.Further data show that this biased inheritance of chromosomal DNA by progeny cells is accompanied by an asymmetric distribution of DNA damage response(DDR),and this asymmetric DDR occurs mainly on telomeres.In terms of mechanism,this study found that the ATR/CHK1 signaling pathway plays an important role in the non-random DNA segregation mediated by asymmetric distribution of telomeric DNA damage.In addition,using living cell image our team observe the clean daughter cell inheriting no DNA damage keeping gemomic stability while the daughter cell carrying the damaged DNA experiences cell cycle arrest or cell death.The research on the non-random segregation of damaged DNA not only provides insights into the maintenance of genomic stability of replication stress-induced cancer cell populations,but also provides new ideas for the development of new cancer diagnostic and therapeutic approaches.In summary,this study first discovered the asymmetric division of DNA damage response after mitosis.The DNA damage response of this asymmetric division is preferentially located on telomeres and depends on the ATR/CHK1 signaling pathway during mitosis.More importantly,we found that asymmetric division of DNA damage responses promotes non-random DNA segregation and may be a potential mechanism for non-random DNA segregation.