Molecular Cell
Volume 71, Issue 1, 5 July 2018, Pages 11-24.e7
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Article
ATRX Promotes DNA Repair Synthesis and Sister Chromatid Exchange during Homologous Recombination

https://doi.org/10.1016/j.molcel.2018.05.014Get rights and content
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Highlights

  • ATRX functions during HR-mediated repair of exogenously induced DNA breaks

  • ATRX, PCNA, and RFC-1 promote extended repair synthesis and sister chromatid exchange

  • ATRX partners with DAXX to deposit histone H3.3 during extended repair synthesis

  • ATRX−/− tumors use HR with limited repair synthesis and no sister chromatid exchange

Summary

ATRX is a chromatin remodeler that, together with its chaperone DAXX, deposits the histone variant H3.3 in pericentromeric and telomeric regions. Notably, ATRX is frequently mutated in tumors that maintain telomere length by a specific form of homologous recombination (HR). Surprisingly, in this context, we demonstrate that ATRX-deficient cells exhibit a defect in repairing exogenously induced DNA double-strand breaks (DSBs) by HR. ATRX operates downstream of the Rad51 removal step and interacts with PCNA and RFC-1, which are collectively required for DNA repair synthesis during HR. ATRX depletion abolishes DNA repair synthesis and prevents the formation of sister chromatid exchanges at exogenously induced DSBs. DAXX- and H3.3-depleted cells exhibit identical HR defects as ATRX-depleted cells, and both ATRX and DAXX function to deposit H3.3 during DNA repair synthesis. This suggests that ATRX facilitates the chromatin reconstitution required for extended DNA repair synthesis and sister chromatid exchange during HR.

Keywords

double-strand breaks
homologous recombination
ATRX
DAXX
H3.3

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