Eukaryotes possess mechanisms to limit crossing over during homologous recombination, thus avoiding possible chromosomal rearrangements. We show here that budding yeast Mph1, an ortholog of human FancM helicase, utilizes its helicase activity to suppress spontaneous unequal sister chromatid exchanges and DNA double-strand break-induced chromosome crossovers. Since the efficiency and kinetics of break repair are unaffected, Mph1 appears to channel repair intermediates into a noncrossover pathway. Importantly, Mph1 works independently of two other helicases—Srs2 and Sgs1—that also attenuate crossing over. By chromatin immunoprecipitation, we find targeting of Mph1 to double-strand breaks in cells. Purified Mph1 binds D-loop structures and is particularly adept at unwinding these structures. Importantly, Mph1, but not a helicase-defective variant, dissociates Rad51-made D-loops. Overall, the results from our analyses suggest a new role of Mph1 in promoting the noncrossover repair of DNA double-strand breaks.

Two BRCA2 ‐like sequences are present in the Arabidopsis genome. Both genes are expressed in flower buds and encode nearly identical proteins, which contain four BRC motifs. In a yeast two‐hybrid assay, the Arabidopsis Brca2 proteins interact with Rad51 and Dmc1. RNAi constructs aimed at silencing the BRCA2 genes at meiosis triggered a reproducible sterility phenotype, which was associated with dramatic meiosis alterations. We obtained the same phenotype upon introduction of RNAi constructs aimed at silencing the RAD51 gene at meiosis in dmc1 mutant plants. The meiotic figures we observed strongly suggest that homologous recombination is highly disturbed in these meiotic cells, leaving aberrant recombination events to repair the meiotic double‐strand breaks. The ‘ brca2 ’ meiotic phenotype was eliminated in spo11 mutant plants. Our experiments point to an essential role of Brca2 at meiosis in Arabidopsis . We also propose a role for Rad51 in the dmc1 context.

Chromosome arm aneuploidies (CAAs) are pervasive in cancers. However, how they affect cancer development, prognosis and treatment remains largely unknown. Here, we analyse CAA profiles of 23,427 tumours, identifying aspects of tumour evolution including probable orders in which CAAs occur and CAAs predicting tissue-specific metastasis. Both haematological and solid cancers initially gain chromosome arms, while only solid cancers subsequently preferentially lose multiple arms. 72 CAAs and 88 synergistically co-occurring CAA pairs multivariately predict good or poor survival for 58% of 6977 patients, with negligible impact of whole-genome doubling. Additionally, machine learning identifies 31 CAAs that robustly alter response to 56 chemotherapeutic drugs across cell lines representing 17 cancer types. We also uncover 1024 potential synthetic lethal pharmacogenomic interactions. Notably, in predicting drug response, CAAs substantially outperform mutations and focal deletions/amplifications combined. Thus, CAAs predict cancer prognosis, shape tumour evolution, metastasis and drug response, and may advance precision oncology.

A cell-penetrating lupus anti-DNA antibody inhibits DNA repair, sensitizes cancer cells to DNA-damaging therapy in vitro and in vivo, and is synthetically lethal to BRCA2-deficient human cancer cells.