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bioRxiv · 10.64898/2026.02.20.706968

Defective BRCA1-mediated DNA end resection drives tandem duplication formation and FANCM synthetic lethality

Scully, R.·Namrata, N.·Marin Gonzalez, A.·Menghi, F.·Nguyen, D.·Willis, N.·Wientjens, E.·Xia, B.·Jonkers, J.·Liu, E.
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Abstract

AbstractBRCA1-linked cancer genomes contain abundant genome-wide [~]10 kb Group 1 tandem duplications (TDs) that are drivers of tumorigenesis. Group 1 TD formation is recapitulated at a chromosomal Tus/Ter site-specific replication fork barrier in DNA end resection-defective mouse embryonic stem (mES) cells lacking Brca1 exon 11. To explore relationships between DNA end resection and Group 1 TD formation, we analyzed Brca1 coiled coil (CC) domain mutants--separation-of-function alleles that are impaired for homologous recombination but competent for DNA end resection. Notably, Brca1 CC mutants retain the ability to suppress Group 1 TDs in the Tus/Ter system and in a mouse model of Brca1-linked tumorigenesis. These data show that Brca1 CC domain mutant cancers follow a path of tumorigenesis distinct from that of other pathogenic Brca1 alleles. FANCM is a TD co-suppressor, the loss of which is synthetic lethal/sick in combination with Brca1 exon 11 mutation. In contrast, Fancm deletion is well-tolerated by Brca1 CC mutant mES cells. Thus, Group 1 TD formation and Fancm synthetic lethality are linked phenotypes related to defective BRCA1-mediated DNA end resection.

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Scully, R., Namrata, N., Marin Gonzalez, A., Menghi, F., Nguyen, D., Willis, N., Wientjens, E., Xia, B., Jonkers, J., Liu, E.. 2026-02-22. Defective BRCA1-mediated DNA end resection drives tandem duplication formation and FANCM synthetic lethality. https://doi.org/10.64898/2026.02.20.706968

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