Work

EGFR inhibits DNA mismatch repair

Year: 2015

Type: article

Abstract: Safeguarding the integrity of the genome should not be left to chance. Indeed, all organisms have highly effective mechanisms to detect and remove errors and lesions in DNA. DNA mismatch repair (MMR) serves as the final safeguard in assuring the fidelity of DNA replication from bacteria to humans and backstops the nucleotide selection and exonuclease proofreading activities of replicative polymerases (Fig. 1) (1⇓–3). The loss of MMR results in greatly elevated rates of spontaneous mutation, is the underlying cause of Lynch syndrome colon cancer, and is implicated in a subset of sporadic tumors. In its postreplication capacity, MMR functions during S phase in close association with the replication fork. This process is mediated by proliferating cell nuclear antigen protein (PCNA), a lynchpin in regulating access and activity of DNA polymerases and other proteins involved in replication, repair, and recombination (4). EGFR, a member of the HER family of receptor tyrosine kinases (RTKs) that span the plasma membrane, regulates cell proliferation, differentiation, and motility in response to extracellular ligands (e.g., EGF) (5, 6). Ligand binding promotes dimerization and allosteric activation of cytoplasmic kinase domains. Autophosphorylation initiates signaling cascades involving RAS/MAPK, PI(3)K/Akt, Jak/STAT, and others. EGFR also translocates to the nucleus where it influences replication, repair, and transcription and is linked to poor prognoses in several malignancies, but molecular mechanisms are largely unknown (7, 8). In the nucleus, EGFR phosphorylates PCNA, increasing its stability (9). This would be expected to have important consequences, but the functional significance was unclear until now. In PNAS, Ortega et al. reveal that phosphorylation of PCNA by EGFR inhibits MMR in cells and switches DNA synthesis in vitro from high-fidelity to error-prone (Fig. 2 … [↵][1]1To whom correspondence should be addressed. Email: peggyh{at}niddk.nih.gov. [1]: #xref-corresp-1-1

Source: Proceedings of the National Academy of Sciences

DOI: 10.1073/pnas.1505168112

Authors: Peggy Hsieh, Alexander H. Pearlman

Institutions: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases

Language: English

Topic: DNA Repair Mechanisms

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: green

Funder: National Institutes of Health