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An emerging picture of FANCJ's role in G4 resolution to facilitate DNA replication - PubMed

  • ️Fri Jan 01 2021

An emerging picture of FANCJ's role in G4 resolution to facilitate DNA replication

Robert M Brosh Jr et al. NAR Cancer. 2021.

Abstract

A well-accepted hallmark of cancer is genomic instability, which drives tumorigenesis. Therefore, understanding the molecular and cellular defects that destabilize chromosomal integrity is paramount to cancer diagnosis, treatment and cure. DNA repair and the replication stress response are overarching paradigms for maintenance of genomic stability, but the devil is in the details. ATP-dependent helicases serve to unwind DNA so it is replicated, transcribed, recombined and repaired efficiently through coordination with other nucleic acid binding and metabolizing proteins. Alternatively folded DNA structures deviating from the conventional anti-parallel double helix pose serious challenges to normal genomic transactions. Accumulating evidence suggests that G-quadruplex (G4) DNA is problematic for replication. Although there are multiple human DNA helicases that can resolve G4 in vitro, it is debated which helicases are truly important to resolve such structures in vivo. Recent advances have begun to elucidate the principal helicase actors, particularly in cellular DNA replication. FANCJ, a DNA helicase implicated in cancer and the chromosomal instability disorder Fanconi Anemia, takes center stage in G4 resolution to allow smooth DNA replication. We will discuss FANCJ's role with its protein partner RPA to remove G4 obstacles during DNA synthesis, highlighting very recent advances and implications for cancer therapy.

Published by Oxford University Press on behalf of NAR Cancer 2021.

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Figures

Figure 1.
Figure 1.

G4 binding pocket, catalytic domain, mapped protein interaction sites, and sites for post-translational modifications of FANCJ. Certain key residues are shown, but not all for simplicity. Lys 141 and Lys142 are implicated in G4 binding. The nuclear localization sequence (NLS) and Fe-S domain are comprised by residues 159–174 and residues 270–263, respectively. The conserved PCNA interaction motif (PIP) corresponds to residues 1001–1017. FANCJ directly binds to the RPA70 subunit of the RPA heterotrimer. The FANCJ Q25A substitution disables the ability of FANCJ to effectively dimerize. The binding site on FANCJ for MSH5 (not shown) has not yet been mapped. See text for additional details and references.

Figure 2.
Figure 2.

Factors that may contribute to FANCJ’s unique requirement to resolve G4 DNA structures to enable smooth cellular DNA replication of the leading and lagging strands. (A) FANCJ unique ability to efficiently resolve intramolecular G4 DNA. (B) FANCJ expression abundance in a cell-type or tissue-specific manner. (C) FANCJ’s protein partnerships with factors directly involved in replication (e.g. RPA). (D) FANCJ’s post-translational modifications affect catalytic function or replisome association. Factors are not mutually exclusive and may influence one another.

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