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Mechanism for Synthetic Lethality in BRCA-Deficient Cancers: No Longer Lagging Behind

Niek van Wietmarschen1, Andre Nussenzweig1

  • 1Laboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda MD.

Molecular Cell
|September 23, 2018
PubMed

Insights

Poly (ADP-ribose) polymerase (PARP) enzymes sense incomplete Okazaki fragments, revealing new insights into DNA single-strand break origins in healthy cells. This discovery impacts understanding of genome instability in BRCA1/BRCA2-deficient cancers.

Area of Science:

  • Molecular Biology
  • DNA Repair Mechanisms
  • Cancer Genomics

Background:

  • Okazaki fragments are short DNA sequences synthesized during replication.
  • PARP enzymes are involved in DNA repair pathways.
  • BRCA1/BRCA2 mutations are linked to hereditary breast and ovarian cancers.

Purpose of the Study:

  • To investigate the role of PARP in sensing Okazaki fragments.
  • To elucidate the mechanism of single-strand break formation in normal cells.
  • To understand the contribution of Okazaki fragment processing to genome instability in BRCA-deficient cancers.

Main Methods:

  • Review of recent studies on PARP function.
  • Analysis of DNA repair pathways.
  • Correlation of Okazaki fragment processing with cancer genomics.

Main Results:

  • PARP acts as a sensor for incompletely processed Okazaki fragments.
  • This sensing mechanism influences the origin of single-strand breaks in unperturbed cells.
  • Unligated Okazaki fragments may initiate homologous recombination repair.

Conclusions:

  • Recent findings redefine the role of PARP in DNA metabolism.
  • Incomplete Okazaki fragment processing is a potential source of genome instability.
  • This has implications for understanding and treating BRCA1/BRCA2-deficient cancers.

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