Okazaki fragment maturation involves α-segment error editing by the mammalian FEN1/MutSα functional complex

Area of Science:

• Molecular Biology
• Genetics
• Cancer Research

Background:

• DNA polymerase alpha (Pol α) synthesizes Okazaki fragments with lower fidelity than other polymerases.
• Proofreading mechanisms are crucial for maintaining genomic stability during DNA replication.

Purpose of the Study:

• To investigate the role of flap endonuclease 1 (FEN1) in correcting replication errors made by Pol α.
• To identify the molecular mechanisms underlying Pol α-associated error correction.

Main Methods:

• Investigated the interaction between FEN1 and MSH2.
• Assessed the nuclease activity of FEN1 on DNA substrates with mismatches.
• Analyzed mouse cells and mice with FEN1 mutations for AEE deficiency, mutator phenotype, and cancer susceptibility.

Main Results:

• FEN1's exonuclease activity excises Pol α replication errors via a MutSα-dependent pathway (Pol α-segment error editing, AEE).
• MSH2 interacts with FEN1, enhancing its nuclease activity for mismatch removal.
• FEN1 mutations result in AEE deficiency, increased mutation rates, cellular transformation, and cancer susceptibility.

Conclusions:

• FEN1 plays a novel role in a specialized mismatch repair pathway (AEE) for Pol α errors.
• Impaired AEE is a new etiological mechanism contributing to cancer development.