RT Journal Article
SR Electronic
T1 DNA replication timing directly regulates the frequency of oncogenic chromosomal translocations
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.05.29.446276
DO 10.1101/2021.05.29.446276
A1 Peycheva, Mihaela
A1 Neumann, Tobias
A1 Malzl, Daniel
A1 Nazarova, Mariia
A1 Schoeberl, Ursula
A1 Pavri, Rushad
YR 2021
UL http://biorxiv.org/content/early/2021/05/29/2021.05.29.446276.abstract
AB Chromosomal translocations result from the joining of DNA double-strand breaks (DSBs) and frequently cause cancer. Yet, the steps linking DSB formation to DSB ligation remain undeciphered. We report that DNA replication timing (RT), mediated by replication origin activity, directly regulates the genesis of lymphomagenic Myc translocations during antibody maturation in B cells. Reduced levels of the replicative helicase, the minichromosome-maintenance (MCM) complex, decreases translocations and globally abrogates the RT program. Ablating a single replication origin at Myc causes an early-to-late RT switch with major loss of translocations, a phenotype that is reversed by restoring early RT. Finally, this novel RT-regulated mechanism occurs after DSB formation and independently of DSB frequency. Thus, RT constitutes a distinct regulatory event in translocation biogenesis linking DSB formation to DSB ligation.Competing Interest StatementThe authors have declared no competing interest.