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100 years ago, researchers found very tight regions on chromosomes and proposed the concept of isochromatin structures (Montgomery TH. (1901), A study of chromosomes of the germ cells of metazoan. Trans Am Phil Soc. 20: 154-136; Heitz E. (1928). Das heterochromatin der Moose. I. Jahrb Wiss Bot. 69: 762-818)。 One hundred years later, the researchers further discovered that 25 to 90 percent of the chromosome regions on multicellular biological chromosomes have heterosomal structures (Lander et al. (2001). Initial sequencing and analysis of the human genome. Nature, 409: 860-921;Vicient & Casacuberta (2017). Impact of transoposable elements on polyploidy plant genome. Ann. Bot. 120:195-207) and demonstrated that these isochrome structures are directly related to genomic stability, gene expression level regulation, cell growth and division, and cell differentiation (Allshire and Madhani (2018). Ten principles of heterochromatin formation and function. Nature Reviews Molecular Cell Biology. 19: 229-244)。 However, after 100 years of research, the underlying mechanism for producing the structure of heterogeneity is not yet determined.
DNA replication is a core biological event that occurs on chromosomes. When a DNA replication fork moves along chromosome DNA and copies and synthesizes DNA, it hits many endogenetic DNA replication fork pauses. Most of these pauses should be caused by the secondary structure of DNA. Various DNA repeat sequences often form multiple types of DNA secondary structures. Human cell chromosomal DNA has about 300,∽ 500,000 replication fork pauses. The stalled DNA replication fork has been shown to be unstable and requires strict cell regulation to maintain its stability, prevent its collapse, and maintain genomic integrity. Checkpoint (cell cycle test point) has also been shown to be a necessary cell regulation to maintain the stability of the pause replication fork and prevent its collapse. If the stalled DNA replication fork collapses, various genetic variants will be produced. Big data statistics show that 66% of cancers are caused by DNA replication errors (Tomasetti et al. (2017), Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention. Science, 355: 1220-1334)。 The collapse of the DNA replication fork is thought to be the main source of DNA replication errors. However, little progress has been made in this field of research over the past two or three decades, and little is known about the molecular mechanisms by which cell regulation maintains the stability of the paused replication fork.
recently, a study by Kondochun Lab found that when DNA replication forks stopped, the chromosome structure around the paused DNA replication forks became tighter. The team demonstrated that histone deacetylization, H3K9 triple methylation, etc. are important aspects of the closer chromatin structure induced by replication fork pause. Further studies have found that if the tight chromatin structure induced by the pause of the DNA replication fork is destroyed, the DNA replication deconstruction enzyme will leave the DNA replication fork, causing the replication fork to collapse. The study also found that the regulation is not affected by Checkpoint regulation. As a result, the work found a new cell control mechanism parallel to the DNA replication test point (checkpoint) - by regulating the nucleosome, changing histogen modification, forming a closer chromosome structure around the paused replication fork, thus preventing the replication fork from collapsing, gene mutations, cell death, or cancer. This governance mechanism is named "The Chromefork Control": Chromatin Compaction Factoring Stroming Replication Forks (see figure below). Future work will clarify the detailed molecular mechanisms of this cell regulation/research area (including the identification of sensors, mediators, and objectors).
to examine known isochrome regions, there are almost always DNA replication fork pauses/barrier points. Research in the Kondochun laboratory has also shown that these natural replication fork stops activate the Chromsfork Control, causing the region to become more chromosome-tight and become heterochromrome regions (unreliated work). Therefore, based on these findings, they believe that the chromosomal tight structure induced by the replication fork pause should be one of the most fundamental mechanisms or mechanisms for the formation of heterochromics. Once the formation of heterosomal structures is initiated, some other bio-chemical mechanisms are assisted, which eventually result in the formation of heterosomal structures in a particular chromosomal region.
the discovery of The Chromsfork Control will advance understanding of the mechanisms by which isochromatin structures form, as well as the molecular mechanisms of how cells maintain the stability of DNA replication forks and the integrity of the genome.The Chromsfork Control Regulatory Pattern
July 1, 2019, the scientific findings were published online in the internationally renowned journal PNAS. The title of the paper is "Replication fork stalling elicits chromatin compaction for the stability of stalling replication forks". Professor Kong Daochun of Peking University is the co-author of this paper, Postdoctoral Feng Gang of Peking University (now independently studying genomic stability mechanisms at Fujian Medical University) and Ph.D. student Yuan Yue are the co-authors of this paper, and Peking University doctoral students Li Zeyang, Wang Lu, Zhang Bo, Roger Wei and Professor Ji Jianguo of Peking University have made important contributions to this paper. The study was supported by the Peking University-Tsinghua Joint Center for Life Sciences, the National Major Scientific Research Program, the National Key Research and Development Program, the National Natural Science Foundation of China, the National Key Laboratory for Protein and Plant Genetics Research, and the School of Life Sciences of Peking University. (Source: Peking University)
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