Format

Send to

Choose Destination
J Biol Chem. 2013 Oct 11;288(41):29294-304. doi: 10.1074/jbc.M113.504175. Epub 2013 Aug 26.

A biochemical analysis linking APOBEC3A to disparate HIV-1 restriction and skin cancer.

Author information

1
From the Departments of Biological Sciences and Chemistry, Molecular and Computational Biology Section, University of Southern California, Los Angeles, California 90089-2910.

Abstract

Human deoxycytidine deaminase APOBEC3A (Apo3A) acts as an HIV-1 restriction factor in cells of myeloid lineage yet functions separately as a potent mutator for genomic DNA. Apo3A activity and C motif deamination specificity exhibit a striking dependence on pH that reflects these two distinct biological processes. Upon infection of macrophages, HIV-1 induces the formation of autophagosomes, and requires autophagosomes for replication, whereas inhibiting lysosomal fusion indicative of late stage autophagy. Here we show that Apo3A has optimal activity and a strict 5'-YYCR motif specificity in the pH 5.8-6.1 range, characteristic of enclosed autophagosomal membrane compartments, and reflective of the mutation pattern of HIV-1. In contrast to the high activity and narrow specificity of Apo3A at acid pH, a 13-30-fold reduction in specific activity is accompanied by relaxed C deamination specificity at pH 7.4-8. Notably, Apo3A is also expressed in keratinocytes, and is up-regulated in skin lesions. At pH 7.9, we show that Apo3A generates transcription-dependent CC → TT tandem mutations on the non-transcribed strand, a hallmark signature of skin cancer. The biochemical data taken in conjunction with the biological up-regulation of Apo3A in skin lesions suggests that enzyme-catalyzed deaminations at adjacent C sites followed by normal replication generating CC → TT mutations provides an alternative molecular basis for the initiation events in skin cancer in contrast to well established pathways in which CC dimers formed in response to UV radiation either undergo nonenzymatic spontaneous deaminations or aberrant replication.

KEYWORDS:

APOBEC; DNA Damage; Deoxycytidine Deaminase; HIV-1; Mutagenesis; Myeloid Cell; Nucleic Acid Enzymology; Skin Cancer

PMID:
23979356
PMCID:
PMC3795231
DOI:
10.1074/jbc.M113.504175
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center