Human APOBEC3A Isoforms Translocate to the Nucleus and Induce DNA Double Strand Breaks Leading to Cell Stress and Death

Mußil, Bianka; Suspène, Rodolphe; Aynaud, Marie-Ming; Gauvrit, Anne; Vartanian, Jean‐Pierre; Wain‐Hobson, Simon

doi:10.1371/journal.pone.0073641

Cited by 80 publications

(110 citation statements)

References 117 publications

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“…4D) (32, 54). Suspene et al and Mussil et al (39,54) demonstrated that A3A hypermutates host nuclear gene loci such as TP53 and c-myc in activated T cells and UGI-expressing 293T cells. Because robust E2 hypermutation was detected in the A3A-and UGI-expressing W12 cells (Fig.…”

Section: Induction Of Apobec3 Genes By Ifn-␤ Stimulationmentioning

confidence: 99%

“…We analogously speculate that uracil bases in the E2 gene generated by A3s may result in DNA strand breaks, leading to viral DNA integration. Moreover, it was recently reported that A3A and A3B expression induces DNA double-strand breaks and genomic instability (13,54,56). DNA strand breaks in viral DNA and host genomic DNA may synergistically increase the chance of viral DNA integration.…”

Section: Induction Of Apobec3 Genes By Ifn-␤ Stimulationmentioning

confidence: 99%

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APOBEC3 Deaminases Induce Hypermutation in Human Papillomavirus 16 DNA upon Beta Interferon Stimulation

Wang

Wakae

Kitamura

et al. 2014

J Virol

101

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A polipoprotein B mRNA-editing catalytic polypeptide (APOBEC) proteins are a family of proteins that share cytidine deaminase activity of DNA and RNA. In humans, the APOBEC family is composed of at least 11 members, including activation-induced cytidine deaminase (AID) and APOBEC1, -2, -3A, -3B, -3C, -3DE, -3F, -3G, -3H, and -4 (1, 2). AID introduces cytidine (C)-to-uracil (U) conversion in immunoglobulin (Ig) genes, a step that is further catalyzed by downstream DNA repair machineries, including base excision repair (BER), mismatch repair, and nonhomologous end-joining repair, to trigger somatic hypermutation, class switch recombination, gene conversion, and chromosomal translocation (3-6). AID also introduces mutations in non-Ig gene loci, such as c-Myc and Bcl-6, although less frequently than in Ig genes (3, 7). Recent studies have suggested that APOBEC3 protein (A3) deaminase activity is responsible for a novel type of mutations called kataegis in multiple human cancers, including cancers of the bladder, cervix, lung, head and neck, and breast (8-13).A3s are antiviral factors against viruses and transposable elements that use reverse transcription during their life cycle (1, 2, 14-16). The antiviral functions of A3s have been extensively studied for human immunodeficiency virus type 1 (HIV-1) and hepatitis B virus (HBV). APOBEC3G (A3G) physically associates with viral RNP complexes, including viral genomic RNA, gag protein (in the case of HIV-1), and P and core protein (in the case of HBV), and is encapsidated into a nucleocapsid, thereby inhibiting reverse transcription in infected cells (2,14,17). Moreover, A3G-induced hypermutation in viral DNA leads to inhibition of HIV-1 replication by either BER-mediated DNA degradation or accumulation of destructive mutations in the viral genome (16,(18)(19)(20). How C-to-U conversion in cellular or viral DNA is converted into different genetic alterations (hypermutation, recombination, and DNA degradation) remains unknown.Human papillomaviruses (HPVs) are small double-stranded DNA viruses infecting epithelial cells. A subset of mucosal HPVs is recognized as a causative agent of cervical cancer (21, 22), among which HPV16 accounts for at least 50% of cervical cancer cases worldwide (23). The HPV16 genome is a 7.9-kb closed circular DNA and is composed of at least 8 open reading frames (E1, E2, E4, E5, E6, E7, L1, and L2) as well as the noncoding long control region (LCR). LCR contains the replication origin and the P 97 promoter responsible for transcription of the E6 and E7 genes. E6 and E7 are viral oncoproteins that degrade p53 and retinoblastoma proteins, respectively, and their enhanced expression is required for cellular transformation (22). In its normal life cycle, HPV16 infects the basal cells of cervical epithelia and establishes their genomes as extrachromosomal episomes. In invasive cervical cancer, however, the viral DNA is frequently integrated into the host chromosome, which generally leads to constitutive expression of E6 and E7. The viral DNA integrat...

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Section: Induction Of Apobec3 Genes By Ifn-␤ Stimulationmentioning

confidence: 99%

Section: Induction Of Apobec3 Genes By Ifn-␤ Stimulationmentioning

confidence: 99%

APOBEC3 Deaminases Induce Hypermutation in Human Papillomavirus 16 DNA upon Beta Interferon Stimulation

Wang

Wakae

Kitamura

et al. 2014

J Virol

101

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“…Thus, the potential exists for these proteins to deaminate cytidine residues of chromosomal DNA. The overexpression of A3A in cultured cells has been shown by some investigators to result in mutation of both nuclear and mitochondrial DNA (Landry et al, 2011;Suspène et al, 2011a;Aynaud et al, 2012;Lackey et al, 2013;Mussil et al, 2013). Moreover, ecotopic expression of A3A in HEK293 cells is generally toxic to cells.…”

Section: Dna Damage and A3amentioning

confidence: 99%

Role of the single deaminase domain APOBEC3A in virus restriction, retrotransposition, DNA damage and cancer

Wang

Schmitt

Guo

et al. 2016

Journal of General Virology

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“…A3A notably is able to hypermutate nuclear DNA (nuDNA) resulting in the formation of double-stranded DNA breaks (DSBs) and apoptosis [2][3][4] . In addition, A3A could deaminate DNA molecules harbouring a variety of 5-oxidized cytidine bases including 5-methylcytidine (5Me-dC; refs 5-7).…”

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confidence: 99%

A prevalent cancer susceptibility APOBEC3A hybrid allele bearing APOBEC3B 3′UTR enhances chromosomal DNA damage

et al. 2014

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Human APOBEC3A (A3A) cytidine deaminase is a host enzyme that can introduce mutations into chromosomal DNA. As APOBEC3B (A3B) encodes a C-terminal catalytic domain B91% identical to A3A, we examined its genotoxic potential as well as that of a highly prevalent chimaeric A3A-A3B deletion allele (DA3B), which is linked to a higher odds ratio of developing breast, ovarian and liver cancer. Interestingly, breast cancer genomes from DA3B À / À patients show a higher overall mutation burden. Here it is shown that germline A3B can hypermutate nuclear DNA, albeit less efficiently than A3A. Chimaeric A3A mRNA resulting from DA3B was more stable, resulting in higher intracellular A3A levels and greater DNA damage. The cancer burden implied by the higher A3A levels could be considerable given the high penetration of the DA3B allele in South East Asia.

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Human APOBEC3A Isoforms Translocate to the Nucleus and Induce DNA Double Strand Breaks Leading to Cell Stress and Death

Cited by 80 publications

References 117 publications

APOBEC3 Deaminases Induce Hypermutation in Human Papillomavirus 16 DNA upon Beta Interferon Stimulation

APOBEC3 Deaminases Induce Hypermutation in Human Papillomavirus 16 DNA upon Beta Interferon Stimulation

Role of the single deaminase domain APOBEC3A in virus restriction, retrotransposition, DNA damage and cancer

A prevalent cancer susceptibility APOBEC3A hybrid allele bearing APOBEC3B 3′UTR enhances chromosomal DNA damage

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