Authors: Yi-Li Feng, Qian Liu, Ruo-Dan Chen, Si-Cheng Liu, Zhi-Cheng Huang, Kun-Ming Liu, Xiao-Ying Yang, An-Yong Xie
Published: 2022-07-25
DOI: 10.1038/s41467-022-32011-x
Source: Full article
AbstractAnalysis of human cancer genome sequences has revealed specific mutational signatures associated withBRCA1-deficient tumors, but the underlying mechanisms remain poorly understood. Here, we show that one-ended DNA double strand breaks (DSBs) converted from CRISPR/Cas9-induced nicks by DNA replication, not two-ended DSBs, cause more characteristic chromosomal aberrations and micronuclei inBrca1-deficient cells than in wild-type cells. BRCA1 is required for efficient homologous recombination of these nick-converted DSBs and suppresses bias towards long tract gene conversion and tandem duplication (TD) mediated by two-round strand invasion in a replication strand asymmetry. However, aberrant repair of these nick-converted one-ended DSBs, not that of two-ended DSBs inBrca1-deficient cells, generates mutational signatures such as small indels with microhomology (MH) at the junctions, translocations and small MH-mediated TDs, resembling those inBRCA1-deficient tumors. These results suggest a major contribution of DNA nicks to mutational signatures associated withBRCA1deficiency in cancer and the underlying mechanisms.