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Mol Cell. 2019 Sep 19;75(6):1286-1298.e12. doi: 10.1016/j.molcel.2019.07.018. Epub 2019 Aug 28.

Poly(ADP-Ribose) Polymerase 2 Recruits Replication Protein A to Sites of LINE-1 Integration to Facilitate Retrotransposition.

Author information

1
Department of Gene Mechanisms, Graduate School of Biostudies, Kyoto University, Kyoto 606-8501, Japan; Department of Stress Response, Graduate School of Biostudies, Kyoto University, Kyoto 606-8501, Japan; Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109-5618, USA. Electronic address: miyoshi.tomoichiro.5e@kyoto-u.ac.jp.
2
Department of Gene Mechanisms, Graduate School of Biostudies, Kyoto University, Kyoto 606-8501, Japan; Department of Stress Response, Graduate School of Biostudies, Kyoto University, Kyoto 606-8501, Japan.
3
Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109-5618, USA; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109-5618, USA. Electronic address: moranj@umich.edu.

Abstract

Long interspersed element-1 (LINE-1 or L1) retrotransposition poses a threat to genome integrity, and cells have evolved mechanisms to restrict retrotransposition. However, how cellular proteins facilitate L1 retrotransposition requires elucidation. Here, we demonstrate that single-strand DNA breaks induced by the L1 endonuclease trigger the recruitment of poly(ADP-ribose) polymerase 2 (PARP2) to L1 integration sites and that PARP2 activation leads to the subsequent recruitment of the replication protein A (RPA) complex to facilitate retrotransposition. We further demonstrate that RPA directly binds activated PARP2 through poly(ADP-ribosyl)ation and can protect single-strand L1 integration intermediates from APOBEC3-mediated cytidine deamination in vitro. Paradoxically, we provide evidence that RPA can guide APOBEC3A, and perhaps other APOBEC3 proteins, to sites of L1 integration. Thus, the interplay of L1-encoded and evolutionarily conserved cellular proteins is required for efficient retrotransposition; however, these interactions also may be exploited to restrict L1 retrotransposition in the human genome.

KEYWORDS:

APOBEC3 proteins; LINE-1; cytidine deamination; integration; mobile genetic element; poly(ADP-ribose) polymerase 2; replication protein A complex; retrotransposition; retrotransposon

PMID:
31473101
PMCID:
PMC6754305
[Available on 2020-09-19]
DOI:
10.1016/j.molcel.2019.07.018

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