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Passenger hotspot mutations in cancer driven by APOBEC3A and mesoscale genomic features

Buisson, Rémi, Langenbucher, Adam, Bowen, Danae, Kwan, Eugene E., Benes, Cyril H., Zou, Lee, Lawrence, Michael S.·2019·Science
DOI 10.1126/science.aaw2872PMC PMC6731024
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Abstract

APOBEC3A hairpin passenger hotspots: Genomic features are often examined at extremes to determine the impact of mutations. These genomic regions span from the trinucleotide context to megabases that underlie chromatin and chromosomal features. Examining mutational dynamics at the mesoscale, the intermediate span of the genome, Buisson et al. characterized the mutational dynamics of cancer (see the Perspective by Carter). They found that mutations caused by the APOBEC enzyme in DNA stem-loops, a mesoscale feature of the genome, could drive recurrent mutations. Many of these types of mutations have been identified as likely drivers of cancer. However, APOBEC-generated mutations outside of stem-loops were more likely to be cancer driver mutations, providing a genomic context for separating cancer driver from passenger mutations. Science , this issue p. eaaw2872 ; see also p. 1228

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  • A3A showed a preferred dinucleotide UC motif for editing.

    “A3A showed a preferred dinucleotide UC motif, consistent with previous reports about the preferred motif for A3A-mediated editing of cellular RNA targets25,54.”

    From The roles of APOBEC-mediated RNA editing in SARS-CoV-2 mutations, replication and fitness (2022) · cites this paper as [54]

    In “APOBEC3A prefers substrate sites in DNA stem-loops” (page unavailable), the paper links A3A activity to TpC dinucleotides in DNA. “Sequence contexts regulating APOBEC3A and mutation accumulation in tumors” further identifies preferred DNA sequence contexts. It does not establish a UC preference for editing cellular RNA targets; the supported finding concerns the analogous DNA motif. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Some cellular RNA targets with stem-loop structures are favored by A3A and A1 editing.

    “Prior reports show that some cellular RNA targets with stem-loop structures are favored by A3A and A1 editing25,28,34,54.”

    From The roles of APOBEC-mediated RNA editing in SARS-CoV-2 mutations, replication and fitness (2022) · cites this paper as [54]

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Metadata

Authors
Buisson, R., Langenbucher, A., Bowen, D., Kwan, E. E., Benes, C. H., Zou, L., & Lawrence, M. S.
Affiliations
  • Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
  • Department of Biological Chemistry, Center for Epigenetics and Metabolism, Chao Family Comprehensive Cancer Center, University of California, Irvine, CA, USA.
ORCID
Venue
Science
Publisher
American Association for the Advancement of Science (AAAS)
Published
2019-06-28
Volume
364
Issue
6447
ISSN
  • 0036-8075
  • 1095-9203
DOI
10.1126/science.aaw2872
PMC
PMC6731024
Cited by
318
References
6
Language
en
Funders
NIH Office of the Director (1K99CA212154, GM076388, CA197779)

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