Mitotic microhomology-mediated break-induced replication promotes chromoanasynthesis

Ngo, Greg H. P., Cleal, Kez, Seifan, Sara, Miklos, Vanda, Barwacz, Szymon A., Ruis, Brian L., Kamranvar, Siamak A., Grimstead, Julia W., Liu, Ying, Hendrickson, Eric A. and Baird, Duncan M. ORCID: https://orcid.org/0000-0001-8408-5467 2026. Mitotic microhomology-mediated break-induced replication promotes chromoanasynthesis. Nature Communications 10.1038/s41467-026-70086-y

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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.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Schools > Medicine Research Institutes & Centres > Wales Cancer Research Centre (WCRC)
Publisher:	Nature Research
ISSN:	2041-1723
Date of First Compliant Deposit:	9 March 2026
Date of Acceptance:	13 February 2026
Last Modified:	10 Mar 2026 16:25
URI:	https://orca.cardiff.ac.uk/id/eprint/185620

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