APOBEC3B Nuclear Localization Requires Two Distinct N-Terminal Domain Surfaces

Daniel J. Salamango, Jennifer L. McCann, Özlem Demir, William L. Brown, Rommie E. Amaro, Reuben S. Harris

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

The APOBEC3 family of cytosine deaminases catalyzes the conversion of cytosines-to-uracils in single-stranded DNA. Traditionally, these enzymes are associated with antiviral immunity and restriction of DNA-based pathogens. However, a role for these enzymes in tumor evolution and metastatic disease has also become evident. The primary APOBEC3 candidate in cancer mutagenesis is APOBEC3B (A3B) for three reasons: (1) A3B mRNA is upregulated in several different cancers, (2) A3B expression and mutational loads correlate with poor clinical outcomes, and (3) A3B is the only family member known to be constitutively nuclear. Previous studies have mapped non-canonical A3B nuclear localization determinants to a single surface-exposed patch within the N-terminal domain (NTD). Here, we show that A3B has an additional, distinct, surface-exposed NTD region that contributes to nuclear localization. Disruption of residues within the first 30 amino acids of A3B (import surface 1) or loop 5/α-helix 3 (import surface 2) completely abolish nuclear localization. These import determinants also graft into NTDs of related family members and mediate re-localization from cell-wide-to-nucleus or cytoplasm-to-nucleus. These findings demonstrate that both sets of residues are required for non-canonical A3B nuclear localization and describe unique surfaces that may serve as novel therapeutic targets.

Original languageEnglish (US)
Pages (from-to)2695-2708
Number of pages14
JournalJournal of Molecular Biology
Volume430
Issue number17
DOIs
StatePublished - Aug 17 2018

Bibliographical note

Funding Information:
We thank Gabriel Starrett and Christopher Richards for intellectual discussion. D.J.S. received salary support from the University of Minnesota Craniofacial Research Training (MinnCResT) program (NIH T90DE022732). This work was supported by NIAID R37 AI064046. Support from NIH P41 GM103426 to R.E.A. is gratefully acknowledged. R.S.H. is the Margaret Harvey Schering Land Grant Chair for Cancer Research, a Distinguished University McKnight Professor, and an Investigator of the Howard Hughes Medical Institute.

Funding Information:
We thank Gabriel Starrett and Christopher Richards for intellectual discussion. D.J.S. received salary support from the University of Minnesota Craniofacial Research Training (MinnCResT) program ( NIH T90DE022732 ). This work was supported by NIAID R37 AI064046 . Support from NIH P41 GM103426 to R.E.A. is gratefully acknowledged. R.S.H. is the Margaret Harvey Schering Land Grant Chair for Cancer Research, a Distinguished University McKnight Professor, and an Investigator of the Howard Hughes Medical Institute.

Publisher Copyright:
© 2018 Elsevier Ltd

Keywords

  • APOBEC3B
  • cancer genomic DNA deaminase
  • nuclear import
  • retrovirus restriction factor
  • subcellular localization

Fingerprint

Dive into the research topics of 'APOBEC3B Nuclear Localization Requires Two Distinct N-Terminal Domain Surfaces'. Together they form a unique fingerprint.

Cite this