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CRISPR/Cas9-mediated Targeted Integration In Vivo Using a Homology-mediated End Joining-based Strategy
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PLK1 targets CtIP to promote microhomology-mediated end joining

Hailong Wang1, Zhiyu Qiu1, Bo Liu1

  • 1Beijing Key Laboratory of DNA Damage Response and College of Life Sciences, Capital Normal University, Beijing 100048, China.

Nucleic Acids Research
|September 12, 2018
PubMed

Insights

Mitotic kinases like PLK1, CDK1, and Aurora A promote microhomology-mediated end joining (MMEJ), an error-prone DNA repair pathway. This study reveals how these kinases target CtIP to favor MMEJ, potentially driving cancer progression.

Area of Science:

  • Cellular biology
  • Molecular oncology
  • DNA repair mechanisms

Background:

  • DNA double-strand breaks (DSBs) require precise repair for genome stability.
  • Microhomology-mediated end joining (MMEJ) is an error-prone DSB repair pathway linked to carcinogenesis.
  • Mitotic kinases (PLK1, CDK1, Aurora A) are implicated in MMEJ and often overexpressed in tumors.

Purpose of the Study:

  • To investigate the functional interplay between mitotic kinases and the MMEJ pathway.
  • To elucidate the molecular mechanisms by which PLK1, CDK1, and Aurora A influence DSB repair choices.

Main Methods:

  • Nocodazole-induced mitotic arrest to study DSB repair.
  • Phosphorylation site analysis of the DSB repair factor CtIP.
  • Site-directed mutagenesis to create CtIP phosphorylation mimic mutants.

Main Results:

  • MMEJ is the preferred DSB repair pathway in mitotic-arrested cells.
  • CDK1/Aurora A and PLK1 cooperatively phosphorylate CtIP at distinct sites (Ser327 and Ser723).
  • A CtIP phosphorylation mimic mutant impairs homologous recombination and G2/M checkpoint but promotes MMEJ.

Conclusions:

  • PLK1 targets CtIP to promote error-prone MMEJ over homologous recombination.
  • This mechanism may contribute to the oncogenic roles of these kinases by inactivating the G2/M checkpoint and promoting MMEJ.
  • Findings illuminate novel therapeutic targets for cancer treatment.

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