Alternative solutions and new scenarios for translesion DNA synthesis by human PrimPol

Martínez‐Jiménez, María I.; García-Gómez, Sara; Bębenek, Katarzyna; Sastre-Moreno, Guillermo; Calvo, Patricia A; Díaz-Talavera, Alberto; Kunkel, Thomas A.; Blanco, Luis

doi:10.1016/j.dnarep.2015.02.013

Cited by 62 publications

(89 citation statements)

References 57 publications

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“…Although many proteins might be needed for repriming at persistently stalled forks after HU treatment (5,(9)(10)(11)(12)(15)(16)(17)(18)(19)(20), it has been predicted that at forks elongating across UV lesions, repriming might be better achieved by Okazaki-like replicating complexes at ssDNA stretches (22). In agreement with such a prediction, the dysregulated elongation of the IdU track in Rad51-depleted cells depends on PrimPol, which is a DNA polymerase with primase activity (51). The persistently dysregulated DNA elongation observed in Rad51-depleted cells treated with UV irradiation might promote the more rapid completion of DNA replication reported in Fig.…”

Section: Rad51 Prevents Dysregulated Fork Elongation After Uv Irradiamentioning

confidence: 48%

Rad51 recombinase prevents Mre11 nuclease-dependent degradation and excessive PrimPol-mediated elongation of nascent DNA after UV irradiation

Vallerga

Mansilla

Federico

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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After UV irradiation, DNA polymerases specialized in translesion DNA synthesis (TLS) aid DNA replication. However, it is unclear whether other mechanisms also facilitate the elongation of UVdamaged DNA. We wondered if Rad51 recombinase (Rad51), a factor that escorts replication forks, aids replication across UV lesions. We found that depletion of Rad51 impairs S-phase progression and increases cell death after UV irradiation. Interestingly, Rad51 and the TLS polymerase polη modulate the elongation of nascent DNA in different ways, suggesting that DNA elongation after UV irradiation does not exclusively rely on TLS events. In particular, Rad51 protects the DNA synthesized immediately before UV irradiation from degradation and avoids excessive elongation of nascent DNA after UV irradiation. In Rad51-depleted samples, the degradation of DNA was limited to the first minutes after UV irradiation and required the exonuclease activity of the double strand break repair nuclease (Mre11). The persistent dysregulation of nascent DNA elongation after Rad51 knockdown required Mre11, but not its exonuclease activity, and PrimPol, a DNA polymerase with primase activity. By showing a crucial contribution of Rad51 to the synthesis of nascent DNA, our results reveal an unanticipated complexity in the regulation of DNA elongation across UV-damaged templates.PrimPol | polκ | polη | DNA damage tolerance | DNA replication T he DNA-binding protein Rad51 is a central component of homologous recombination repair (HRR). HRR repairs doublestrand breaks (DSBs) in an error-free way and processes one-ended DSBs to reactivate collapsed replication forks (1). During HRR, DSBs are processed by the 3′-to-5′ exonuclease activity of the double strand break repair nuclease (Mre11) to generate protruding 3′ ssDNA at DSBs. The ssDNA is then coated with Rad51, a factor that catalyzes homology search and strand invasion. The loading and stabilization of Rad51/ssDNA complexes are supported by multiple mediators, such as the tumor suppressor BRCA2 (breast cancer 2) (1). Moreover, Rad51 promotes XPF1-and Exo1-mediated DSB formation after gemcitabine-induced irreversible ribonucleotide reductase inhibition, thus promoting cell death (2). The signals that redirect Rad51 into a DSB formation pathway rather than DSB repair are not yet known.The functions of Rad51 are not limited to the processing/ generation of DSBs. Over the past few years, it has become evident that Rad51 escorts ongoing replication forks regardless of the presence of DSBs (3-5). Specifically, Rad51 protects persistently stalled replication forks from Mre11-mediated nucleolytic degradation and facilitates replication fork restart when the replication-halting agent hydroxyurea (HU) or aphidicolin (APH) is removed (6-19). Such novel functions of Rad51 require many HRR factors, including BCRA2, FANCD2 (Fanconi Anemia Complementation group protein D2), CtIP, BRCA1, and the WRN helicase, but are independent of HRR effectors, such as Rad54 (6, 7). Rad51-dependent fork-restart and fork-protection ...

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Section: Rad51 Prevents Dysregulated Fork Elongation After Uv Irradiamentioning

confidence: 48%

Rad51 recombinase prevents Mre11 nuclease-dependent degradation and excessive PrimPol-mediated elongation of nascent DNA after UV irradiation

Vallerga

Mansilla

Federico

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…3C), the 5′T (covalently linked to the 3′T via a single C6–C4 bond) again sterically overlaps with Gly 74 and Arg 76 . It is conceivable that PrimPol bypasses the (6–4) T-T photoproduct and other bulky DNA lesions by looping them out ( 23 ), possibly in the space between ModN and N-helix.…”

Section: Resultsmentioning

confidence: 99%

Structure and mechanism of human PrimPol, a DNA polymerase with primase activity

et al. 2016

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“…A second DNA polymerase, referred to as PrimPol (primase polymerase), has been reported to act in both the nucleus and in mitochondria. PrimPol is not essential for mtDNA maintenance and may serve a more specialized role, for example, by facilitating mtDNA replication fork progression at lesions or replication blocks, or both (83,84).…”

Section: The Mtdna Replisomementioning

confidence: 99%

Maintenance and Expression of Mammalian Mitochondrial DNA

Gustafsson

Falkenberg

Larsson

2016

Annu. Rev. Biochem.

568

509

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Mammalian mitochondrial DNA (mtDNA) encodes 13 proteins that are essential for the function of the oxidative phosphorylation system, which is composed of four respiratory-chain complexes and adenosine triphosphate (ATP) synthase. Remarkably, the maintenance and expression of mtDNA depend on the mitochondrial import of hundreds of nuclear-encoded proteins that control genome maintenance, replication, transcription, RNA maturation, and mitochondrial translation. The importance of this complex regulatory system is underscored by the identification of numerous mutations of nuclear genes that impair mtDNA maintenance and expression at different levels, causing human mitochondrial diseases with pleiotropic clinical manifestations. The basic scientific understanding of the mechanisms controlling mtDNA function has progressed considerably during the past few years, thanks to advances in biochemistry, genetics, and structural biology. The challenges for the future will be to understand how mtDNA maintenance and expression are regulated and to what extent direct intramitochondrial cross talk between different processes, such as transcription and translation, is important.

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Alternative solutions and new scenarios for translesion DNA synthesis by human PrimPol

Cited by 62 publications

References 57 publications

Rad51 recombinase prevents Mre11 nuclease-dependent degradation and excessive PrimPol-mediated elongation of nascent DNA after UV irradiation

Rad51 recombinase prevents Mre11 nuclease-dependent degradation and excessive PrimPol-mediated elongation of nascent DNA after UV irradiation

Structure and mechanism of human PrimPol, a DNA polymerase with primase activity

Maintenance and Expression of Mammalian Mitochondrial DNA

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