Rad51 recruitment and exclusion of non-homologous end joining during homologous recombination at a Tus/Ter mammalian replication fork barrier

PLoS Genetics
Nicholas A WillisRalph Scully

Abstract

Classical non-homologous end joining (C-NHEJ) and homologous recombination (HR) compete to repair mammalian chromosomal double strand breaks (DSBs). However, C-NHEJ has no impact on HR induced by DNA nicking enzymes. In this case, the replication fork is thought to convert the DNA nick into a one-ended DSB, which lacks a readily available partner for C-NHEJ. Whether C-NHEJ competes with HR at a non-enzymatic mammalian replication fork barrier (RFB) remains unknown. We previously showed that conservative "short tract" gene conversion (STGC) induced by a chromosomal Tus/Ter RFB is a product of bidirectional replication fork stalling. This finding raises the possibility that Tus/Ter-induced STGC proceeds via a two-ended DSB intermediate. If so, Tus/Ter-induced STGC might be subject to competition by C-NHEJ. However, in contrast to the DSB response, where genetic ablation of C-NHEJ stimulates HR, we report here that Tus/Ter-induced HR is unaffected by deletion of either of two C-NHEJ genes, Xrcc4 or Ku70. These results show that Tus/Ter-induced HR does not entail the formation of a two-ended DSB to which C-NHEJ has competitive access. We found no evidence that the alternative end-joining factor, DNA polymerase θ, competes with Tus/...Continue Reading

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Citations

Jul 3, 2019·Nature Reviews. Molecular Cell Biology·Ralph ScullyNicholas A Willis
Jun 15, 2019·FEBS Letters·Kohji Hizume, Hiroyuki Araki
Dec 22, 2020·The Journal of Cell Biology·Riko IshimotoMasatoshi Fujita
Apr 22, 2021·Molecular Cell·Arvind PandayRalph Scully
Jun 21, 2021·Trends in Cell Biology·Connor S Clairmont, Alan D D'Andrea

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Methods Mentioned

BETA
transfection
genotyping
FACS
PCR
HTGTS
transfections
flow cytometry
immunoprecipitation
ChIP

Software Mentioned

Primer
Roche ProbeFinder
GraphPad Prism

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