DNA nicks induce mutational signatures associated with BRCA1 deficiency

Yi-Li Feng (), Qian Liu, Ruo-Dan Chen, Si-Cheng Liu, Zhi-Cheng Huang, Kun-Ming Liu, Xiao-Ying Yang and An-Yong Xie ()
Additional contact information
Yi-Li Feng: Zhejiang University School of Medicine
Qian Liu: Zhejiang University School of Medicine
Ruo-Dan Chen: Zhejiang University School of Medicine
Si-Cheng Liu: Zhejiang University School of Medicine
Zhi-Cheng Huang: Zhejiang University School of Medicine
Kun-Ming Liu: Zhejiang University School of Medicine
Xiao-Ying Yang: Zhejiang University School of Medicine
An-Yong Xie: Zhejiang University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract Analysis of human cancer genome sequences has revealed specific mutational signatures associated with BRCA1-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 in Brca1-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 in Brca1-deficient cells, generates mutational signatures such as small indels with microhomology (MH) at the junctions, translocations and small MH-mediated TDs, resembling those in BRCA1-deficient tumors. These results suggest a major contribution of DNA nicks to mutational signatures associated with BRCA1 deficiency in cancer and the underlying mechanisms.

Date: 2022
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-022-32011-x Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32011-x

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-022-32011-x

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().