Mitotic microhomology-mediated break-induced replication promotes chromoanasynthesis
Greg H P Ngo1, Kez Cleal2, Sara Seifan2
1Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK. NgoG@cardiff.ac.uk.
Nature Communications
|March 3, 2026
Summary
Chromoanasynthesis, a complex chromosomal rearrangement, is driven by microhomology-mediated break-induced replication (MM-BIR) during mitosis. This process, involving MMEJ and BIR, explains extreme mutations in cancers and congenital disorders.
Area of Science:
- Genetics
- Molecular Biology
- Cancer Research
Background:
- Chromoanasynthesis is a complex chromosomal rearrangement (CCR) implicated in cancers and congenital disorders.
- The precise molecular mechanisms generating chromoanasynthesis remain largely unknown.
- Understanding CCRs is crucial for deciphering disease origins.
Purpose of the Study:
- To elucidate the mechanism of chromoanasynthesis generation.
- To characterize ultra-complex mutational events associated with chromoanasynthesis.
- To investigate the role of DNA repair pathways in CCRs.
Main Methods:
- Utilized single-molecule long-read DNA sequencing to analyze complex mutations.
- Focused on events occurring at shortened telomeres and sub-telomeric DNA double-strand breaks.
- Investigated the involvement of microhomology-mediated end-joining (MMEJ) and break-induced replication (BIR) pathways.
Main Results:
- Chromoanasynthesis is generated by microhomology-mediated break-induced replication (MM-BIR) specifically during mitosis.
- A novel pathway involving MMEJ proteins initiating a Polδ-dependent BIR pathway was identified.
- This mitotic MM-BIR pathway is regulated by PIF1, POLD3, and PCNA, and is prone to template switching.
- The pathway can lead to significant genomic locus amplification in a single event.
Conclusions:
- Mitotic MM-BIR is a key driver of chromoanasynthesis and complex chromosomal rearrangements (CCRs).
- This mechanism explains the highly mutagenic nature of chromoanasynthesis.
- Findings have significant implications for understanding the etiology of cancers and congenital disorders.
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