Genome complexity: controls of DNA replications (Introduction)

by David Turell , Friday, March 15, 2024, 18:59 (43 days ago) @ David Turell

Molecular forks direct the action:

https://www.sciencemagazinedigital.org/sciencemagazine/library/item/15_march_2024/41803...

"DNA replication is initiated at multiple loci to ensure timely duplication of eukaryotic genomes. Sister replication forks progress bidirectionally, and replication terminates when two convergent forks encounter one another. To investigate the coordination of replication forks, we developed a replication associated in situ HiC method to capture chromatin interactions involving nascent DNA. We identify more than 2000 fountain-like structures of chromatin contacts in human and mouse genomes, indicative of coupling of DNA replication forks. Replication fork interaction not only occurs between sister forks but also involves forks from two distinct origins to predetermine replication termination. Termination associated chromatin fountains are sensitive to replication stress and lead to coupled forks–associated genomic deletions in cancers. These findings reveal the spatial organization of DNA replication forks within the chromatin context."

Comment: a highly technical article, impossible to edit. They discuss their findings in DNA repair of lesions. An example:

"'The human genome harbors numerous DNA-template lesions or replication barriers that stall replication forks. Moreover, in E. coli, blocking one fork causes a substantial reduction in the replication speed of the other fork. Therefore, it is possible that in mammalian cells, both coupled forks stall when either is impaired. In this context, we observed similar replication speeds for coupled forks. Upon DNA-template lesions, the replisome at the damaged strand may or may not disassemble from chromatin to create more space for DNA repair, whereas the other replisome can mark stalled replication forks and facilitate fork restart at the right position. However, upon global replication stress such as aphidicolin, it becomes more challenging for two failed coupled forks to restart DNA replication. In this context, the two ends of genomic deletions in cancers are distributed similarly around the centers of both types of fountains, implying that the coupled forks may collapse to induce DNA breaks simultaneously. Alternatively, it is also possible that incomplete DNA replication under global replication stress is induced by the disruption of fork coupling. The dual failure of coupled sister forks may be rescued by the firing of neighbor dormant origins, but origin-poor type-II fountains might lead to incomplete DNA replication under global replication stress. This feature is similar to CFSs and RDC genes. Of note, the overlap of type-II fountains and CFSs may also be attributable to the possibility that origin-poor regions support long stretches of type-II fountains and favor fountain detection."

Comment: Skim this and denying design in impossible.