Two Mechanisms of Chromosome Fragility at Replication-termination Sites in Bacteria

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2021 Jun 19

PMID 34144978

Citations 13

Authors

Qian Mei

Devon M Fitzgerald

Jingjing Liu

Jun Xia

John P Pribis

Yin Zhai

Ralf B Nehring

Jacob Paiano

Heyuan Li

Andre Nussenzweig

P J Hastings

Susan M Rosenberg

Affiliations

Soon will be listed here.

Abstract

Chromosomal fragile sites are implicated in promoting genome instability, which drives cancers and neurological diseases. Yet, the causes and mechanisms of chromosome fragility remain speculative. Here, we identify three spontaneous fragile sites in the genome and define their DNA damage and repair intermediates at high resolution. We find that all three sites, all in the region of replication termination, display recurrent four-way DNA or Holliday junctions (HJs) and recurrent DNA breaks. Homology-directed double-strand break repair generates the recurrent HJs at all of these sites; however, distinct mechanisms of DNA breakage are implicated: replication fork collapse at natural replication barriers and, unexpectedly, frequent shearing of unsegregated sister chromosomes at cell division. We propose that mechanisms such as both of these may occur ubiquitously, including in humans, and may constitute some of the earliest events that underlie somatic cell mosaicism, cancers, and other diseases of genome instability.

Citing Articles

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