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Structure-dependent bypass of DNA interstrand crosslinks by translesion synthesis polymerases

The Vinh Ho1, Angelo Guainazzi, Semsi Burak Derkunt

  • 1Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794-3400, USA.

Nucleic Acids Research
|June 14, 2011
PubMed

Insights

DNA interstrand crosslinks (ICLs) are repaired by translesion synthesis (TLS) polymerases. The efficiency of ICL bypass depends on the DNA structure and crosslink length, influencing polymerase selection.

Area of Science:

  • Molecular Biology
  • DNA Repair Mechanisms
  • Cancer Therapeutics

Background:

  • DNA interstrand crosslinks (ICLs) covalently link DNA strands, impeding DNA metabolism.
  • Antitumor agents like cisplatin generate ICLs, necessitating complex repair pathways.
  • Translesion synthesis (TLS) is a common step in human ICL repair pathways.

Purpose of the Study:

  • To investigate the bypass efficiency of Y-family polymerases and Pol ζ on site-specific major groove ICLs.
  • To determine how DNA distortion induced by ICLs affects polymerase activity.
  • To identify factors influencing the ability of polymerases to process ICLs.

Main Methods:

  • Generation of site-specific major groove ICLs in DNA.
  • Assays to study the bypass capabilities of Y-family polymerases and Pol ζ.
  • Analysis of ICL structure and flanking DNA sequence effects on polymerase function.

Main Results:

  • ICL bypass efficiency is influenced by the length of flanking dsDNA and the crosslinking bridge.
  • TLS polymerases can effectively bypass ICLs when properly processed.
  • The specific structure of an ICL dictates which TLS polymerases can read through it.

Conclusions:

  • Appropriate processing allows TLS polymerases to efficiently bypass ICLs.
  • ICL structure is a critical determinant for polymerase selection during DNA repair.
  • Understanding ICL bypass mechanisms can inform cancer therapy strategies.

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