Willis, N. | bioRxiv Science

bioRxiv2026

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

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.

molecular biology↗

bioRxiv2020

Structural requirements for dihydrobenzoxazepinone anthelmintics: actions against medically important and model parasites - Trichuris muris, Brugia malayi and Heligmosomoides polygyrus

Nine hundred million people are infected with the soil-transmitted helminths Ascaris lumbricoides (roundworm), hookworm, and Trichuris trichiura (whipworm). However, low single-dose cure rates of the benzimidazole drugs, the mainstay of preventative chemotherapy for whipworm, together with parasite drug resistance, mean that current approaches may not be able to eliminate morbidity from Trichuriasis. We are seeking to develop new anthelmintic drugs specifically with activity against whipworm as a priority, and previously identified a hit series of dihydrobenzoxazepinone (DHB) compounds that block motility of ex vivo Trichuris muris. Here we report a systematic investigation of the structure-activity relationship of the anthelmintic activity of DHB compounds. We synthesised 47 analogues, which allowed us to define features of the molecules essential for anthelmintic action, as well as broadening the chemotype by identification of dihydrobenzoquinolinones (DBQ) with anthelmintic activity. We investigated the activity of these compounds against other parasitic nematodes, identifying DHB compounds with activity against Brugia malayi and Heligmosomoides polygyrus. We also demonstrated activity of DHB compounds against the trematode Schistosoma mansoni, a parasite that causes schistosomiasis. These results demonstrate the potential of DHB and DBQ compounds for further development as broad-spectrum anthelmintics. Author summaryAround a billion people are infected by the soil transmitted helminths Ascaris, hookworm and whipworm. In the case of whipworm, the benzimidazole drugs, which are distributed to school children in affected areas, have low cure rates. This means that finding an improved treatment for whipworm is a priority. We previously identified five DHB compounds in a screen for new compounds active against whipworm. Here we systematically dissect these molecules, making 47 modified versions of the compounds. This allowed us to define the features of these compounds that are important for activity against whipworm. We also demonstrate activity of DHB compounds against other parasitic nematodes, and against Schistosoma mansoni, a trematode parasite. These results show the potential for further development of DHB compounds as broad-spectrum anthelmintics.

pharmacology and toxicology↗