Common fragile sites (CFSs) are regions susceptible to replication stress and are hotspots for chromosomal instability in cancer. Several features were suggested to underlie CFS instability, however, these features are prevalent across the genome. Therefore, the molecular mechanisms underlying CFS instability remain unclear. Here, we explore the transcriptional profile and DNA replication timing (RT) under mild replication stress in the context of the 3D genome organization. The results reveal a fragility signature, comprised of a TAD boundary overlapping a highly transcribed large gene with APH-induced RT-delay. This signature enables precise mapping of core fragility regions in known CFSs and identification of novel fragile sites. CFS stability may be compromised by incomplete DNA replication and repair in TAD boundaries core fragility regions leading to genomic instability. The identified fragility signature will allow for a more comprehensive mapping of CFSs and pave the way for investigating mechanisms promoting genomic instability in cancer.
Bibliographical noteFunding Information:
This research was supported by grants to B.K. from the Israel Science Foundation (grant No. 176/11), the Israel Science Foundation (grant No. 1284/18), the Israeli Centers of Research Excellence (I-CORE), Gene Regulation in Complex Human Disease, Center No. 41/11, the ISF-NSFC joint program (grant No. 2535/16), and to D.M.G. from the NIH grant GM083337. The authors thank the members of the Kerem lab for thoughtful discussions and advice, Dr. Daniel Vera for bioinformatics analyses, and Dr. Noemie Stanleigh for review and comments on the paper.
© 2020, The Author(s).