2026-03-10 カーディフ大学
＜関連情報＞
- https://www.cardiff.ac.uk/news/view/3031720-new-insights-into-chaotic-chromosome-mutations
- https://www.nature.com/articles/s41467-026-70086-y
有糸分裂マイクロホモロジーを介した切断誘導複製は染色体合成を促進する Mitotic microhomology-mediated break-induced replication promotes chromoanasynthesis
Greg H. P. Ngo,Kez Cleal,Sara Seifan,Vanda Miklos,Szymon A. Barwacz,Brian L. Ruis,Siamak A. Kamranvar,Julia W. Grimstead,Ying Liu,Eric A. Hendrickson & Duncan M. Baird
Nature Communications Published:03 March 2026
DOI:https://doi.org/10.1038/s41467-026-70086-y Unedited version
Abstract
Chromoanasynthesis is a form of complex chromosomal rearrangement (CCR) commonly detected in cancers and congenital disorders, but the mechanism underlying its generation remain elusive. Here we develop a single-molecule long-read DNA sequencing approach to characterise ultra-complex mutational events, consistent with chromoanasynthesis, occurring at shortened telomeres and sub-telomeric DNA double-strand breaks in human cells. Our data reveal that chromoanasynthesis is generated by microhomology-mediated break-induced replication (MM-BIR), occurring specifically in mitosis. Surprisingly, this mitotic pathway involves a collaboration between microhomology-mediated end-joining (MMEJ) and BIR, where MMEJ proteins initiate a Polδ-dependent BIR pathway that is regulated by PIF1, POLD3 and PCNA. This pathway is highly prone to template switching and can generate dramatic amplification of genomic loci in a single event. Our findings help explain the extreme mutagenic nature of chromoanasynthesis and establish mitotic MM-BIR as a key driver of CCRs, with important implications for the origin of cancers and congenital disorders.
