Research Article

A nuclease that mediates cell death induced by DNA damage and poly(ADP-ribose) polymerase-1

See allHide authors and affiliations

Science  07 Oct 2016:
Vol. 354, Issue 6308, aad6872
DOI: 10.1126/science.aad6872

eLetters is an online forum for ongoing peer review. Submission of eLetters are open to all. eLetters are not edited, proofread, or indexed.  Please read our Terms of Service before submitting your own eLetter.

Compose eLetter

Plain text

  • Plain text
    No HTML tags allowed.
  • Web page addresses and e-mail addresses turn into links automatically.
  • Lines and paragraphs break automatically.
Author Information
First or given name, e.g. 'Peter'.
Your last, or family, name, e.g. 'MacMoody'.
Your email address, e.g.
Your role and/or occupation, e.g. 'Orthopedic Surgeon'.
Your organization or institution (if applicable), e.g. 'Royal Free Hospital'.
Statement of Competing Interests

This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.

Enter the characters shown in the image.

Vertical Tabs

  • RE: Quod erat Demonstrandum? A response to Iyer and Aravind: ‘The proof is in the trimer’
    • Ted M. Dawson, Director, Professor, Johns Hopkins University School of Medicine
    • Other Contributors:
      • Yingfei Wang, Assistant Professor, UT Southwestern Medical Center
      • George Umanah, Research Associated, Johns Hopkins University School of Medicine
      • Valina L. Dawson, Professor, Johns Hopkins University School of Medicine

    Iyer’s and Aravind’s argument that MIF may not be a metal dependent nuclease is based on their modeling of the monomeric MIF structure. The DALI server does not compare domains within an oligomeric molecule such as the MIF trimer and as such has substantial shortcomings for analyzing structures like the PD-(D/E)XK superfamily that have variable topologies (1-3). Our analysis of MIF protein structure is based on the solved trimeric structures of MIF and is summarized in the main and supplemental text and Fig. 1E and fig. S3, D to G of Wang et al (4). MIF’s PD-(D/E)XK core residues are conserved among animal orthologs as shown in Fig. S3 of Wang et al., (4). We also showed that MIF’s nuclease function is clearly separated from its well-known tautomerase function consistent with prior studies that have shown that MIF’s tautomerase activity is dispensable for many of its pleiotropic activities (5-7). We did not determine whether MIF’s PD-(D/E)XK motif is conserved between eukaryotes and prokaryotes. This will require further study since the exact sequence of the PD-(D/E)XK core may not be conserved while the active site is maintained in different families of REase (1-3). Thus, it will be important to determine through empiric experiments when during evolution MIF acquired its nuclease activity and whether the tautomerase and nuclease activities are evolutionary separate. In summary, we agree that the MIF monomer has no PDE fold. However, the MIF trimer has a PDE fold. Impor...

    Show More
    Competing Interests: None declared.
  • Quod erat demonstrandum? No restriction endonuclease fold in MIF
    • Lakshminarayan M Iyer, Scientist, National Center for Biotechnology Information
    • Other Contributors:
      • L Aravind, Scientist, National Center for Biotechnology Information

    MIF (1), with previously reported tautomerase activity, is a member of the tautomerase superfamily which does not feature nucleases (2, 3). The authors suggest that MIF is a DNase by claiming a structural relationship to nucleases of the Restriction endonuclease (REase) fold, which frequently but not always contain a PD-(D/E)XK motif (4). They claim that MIF contains three copies of this motif implying that it contains three copies of the REase fold. This is not supported by structure or sequence evidence: 1) A DALI search with the structure of MIF does not recover any REase fold structures with Z-scores suggestive of genuine relationships (Z>3) (5); as expected it recovers several tautomerase superfamily structures (5). 2) The REase fold is topologically unrelated to the tautomerase fold (4), which emerged from an internal duplication of a simple two-strand-helix unit (3, 6). 3) REase fold catalysis requires residues (not conserved in MIF) beyond the metal-coordinating acidic residues of the PD-(D/E)XK (6). Moreover, the aspartates and glutamates identified by the authors (1) are often on opposite ends of different structural elements and not proximal to coordinate a metal ion (Figure 1). 4) These motifs (1), unlike the catalytic prolines of the tautomerases (3), are not well-conserved even among animal orthologs (Figure 1).

    The authors also claim glutamate 22 to be the catalytic residue equivalent to that of the so-called Exonuclease-Endonuclease-Phosphatase...

    Show More
    Competing Interests: None declared.