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Characterizing DNA Repair Processes at Transient and Long-lasting Double-strand DNA Breaks by Immunofluorescence Microscopy
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ATM promotes reversed fork processing during DNA interstrand cross-link repair.

Maria Altshuller1, Victoria A MacKrell1, Jasmine Tzeng1

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This study reveals how DNA interstrand cross-link (ICL) repair uses fork reversal and ATM kinase activation. Protein phosphatase 2A (PP2A) balances this process to prevent DNA damage during replication.

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Area of Science:

  • DNA repair mechanisms
  • Cellular response to DNA damage
  • Molecular cell biology

Background:

  • Replication-coupled DNA interstrand cross-link (ICL) repair involves crucial fork remodeling events.
  • The regulation of fork reversal and restoration during ICL repair remains poorly understood.
  • The Fanconi anemia (FA) pathway is central to resolving ICLs.

Purpose of the Study:

  • To investigate fork dynamics during ICL repair by the FA pathway using cell-free Xenopus egg extracts.
  • To elucidate the regulatory mechanisms governing reversed fork processing during ICL repair.

Main Methods:

  • Utilized cell-free Xenopus egg extracts to model ICL repair.
  • Investigated the role of ataxia telangiectasia-mutated (ATM) kinase in fork reversal.
  • Assessed the functions of EXO1 and DNA2 nucleases in reversed fork resection.
  • Examined the impact of protein phosphatase 2A (PP2A) inhibition on ATM signaling and fork processing.

Main Results:

  • ATM kinase activation is concomitant with fork reversal and promotes resection of the reversed fork intermediate.
  • EXO1 and DNA2 nucleases coordinate to resect the reversed fork, with EXO1 initiating and DNA2 performing further resection.
  • Inhibition of PP2A leads to ATM hyperactivation, excessive reversed fork resection, and aberrant end-joining products.
  • Reversed forks are identified as substrates for ATM activation.

Conclusions:

  • A phospho-regulatory circuit involving ATM and PP2A governs reversed fork processing during ICL repair.
  • This circuit ensures controlled resection of reversed forks, preventing aberrant DNA repair outcomes.
  • The findings provide new insights into the regulation of DNA replication fork dynamics during ICL repair.