Replication Fork Polarity Gradients Revealed by Megabase-Sized U-Shaped Replication Timing Domains in Human Cell Lines

Baker, Antoine; Audit, Benjamin; Chen, Chun-Long; Moindrot, Benoît; Leleu, Antoine; Guilbaud, Guillaume; Rappailles, Aurélien; Vaillant, Cédric; Goldar, Arach; Mongélard, Fabien; d’Aubenton-Carafa, Yves; Hyrien, Olivier; Thermes, Claude; Arnéodo, A.

doi:10.1371/journal.pcbi.1002443

Cited by 71 publications

(219 citation statements)

References 60 publications

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“…4.3.2 in paper I), we note that the neighbordependent rate r impacts on both theθ 0 and θ T [α] coefficients in eqs. (34) to (39). As expected the G + C content still does not depend on the replication fork polarity or gene orientation ( fig.…”

Section: Impact On the T + A And G + C Contentssupporting

confidence: 84%

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Linking the DNA strand asymmetry to the spatio-temporal replication program

et al. 2012

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Abstract. In paper I, we addressed the impact of the spatio-temporal program on the DNA composition evolution in the case of time homogeneous and neighbor-independent substitution rates. But substitution rates do depend on the flanking nucleotides as exemplified in vertebrates where CpG sites are hypermutable so that the substitution rate C → T depends dramatically (ten fold) on whether the cytosine belongs to a CG dinucleotide or not. With the specific goal to account for neighbor-dependence, we revisit our minimal modeling of neutral substitution rates in the human genome. When assuming that r = CpG → T pG and its reverse complement r c = CpG → CpA are (by far) the main neighbor-dependent substitution rates, we demonstrate, using perturbative analysis, that neighbor-dependence does not affect the decomposition of the compositional asymmetry into a transcription-and a replication-associated components, the former increases in magnitude with transcription rate and changes sign with gene orientation, whereas the latter is proportional to the replication fork polarity. Indeed the neighbor dependence case differs from the neighbor-independent model by an additional source term related to the CG dinucleotide content in both the transcription and replication-associated components. We finally discuss the case of time-dependent substitution rates confirming as a very general result the fact that the skew can still be decomposed into a transcription-and a replication-associated components.

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Section: Impact On the T + A And G + C Contentssupporting

confidence: 84%

“…(39) As compared to the neighbor-independent model (see sect. 4.3.2 in paper I), we note that the neighbordependent rate r impacts on both theθ 0 and θ T [α] coefficients in eqs.…”

Section: Impact On the T + A And G + C Contentsmentioning

confidence: 99%

Linking the DNA strand asymmetry to the spatio-temporal replication program

et al. 2012

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“…By using an approach that determines the replication fork polarity (FP) as the derivative of the replication timing (RT) (Baker et al 2012;Haradhvala et al 2016;Morganella et al 2016;Seplyarskiy et al 2016), we predicted for each genomic region whether the reference strand is replicated more frequently as leading (FP > 0) or lagging (FP < 0). Briefly, FP values reflect the ratio of the frequencies of passages of the replication fork in forward and reverse directions relative to the reference strain.…”

Section: Stand-specific Mutational Patterns In Cancers With Mutated Pmentioning

confidence: 99%

Human mismatch repair system balances mutation rates between strands by removing more mismatches from the lagging strand

et al. 2017

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Mismatch repair (MMR) is one of the main systems maintaining fidelity of replication. Differences in correction of errors produced during replication of the leading and the lagging DNA strands were reported in yeast and in human cancers, but the causes of these differences remain unclear. Here, we analyze data on human cancers with somatic mutations in two of the major DNA polymerases, delta and epsilon, that replicate the genome. We show that these cancers demonstrate a substantial asymmetry of the mutations between the leading and the lagging strands. The direction of this asymmetry is the opposite between cancers with mutated polymerases delta and epsilon, consistent with the role of these polymerases in replication of the lagging and the leading strands in human cells, respectively. Moreover, the direction of strand asymmetry observed in cancers with mutated polymerase delta is similar to that observed in MMR-deficient cancers. Together, these data indicate that polymerase delta (possibly together with polymerase alpha) contributes more mismatches during replication than its leading-strand counterpart, polymerase epsilon; that most of these mismatches are repaired by the MMR system; and that MMR repairs about three times more mismatches produced in cells during lagging strand replication compared with the leading strand.

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“…The difference between the results is likely due to differences in how fp is measured. The only assumption made by the method we use is that replication fork velocity is nearly constant throughout the genome Baker et al 2012), and this assumption has been confirmed experimentally Baker et al 2012). Still, the strand asymmetry of TpCpW→K de novo mutations in a larger joined data set (Francioli et al 2015;Wong et al 2016) yielded a significant 1.17-fold difference between strands (Pvalue = 0.0174).…”

Section: Wwwgenomeorgmentioning

confidence: 67%

“…A computational approach has been developed to discriminate, by determining the prevalent direction of the replication fork at each genomic region, between the leading and the lagging DNA strands Baker et al 2012;Haradhvala et al 2016;Seplyarskiy et al 2016), providing a powerful tool to investigate strand-biased mechanisms that give rise even to dispersed mutations Baker et al 2012;Haradhvala et al 2016;Morganella et al 2016;Nik-Zainal et al 2016;Seplyarskiy et al 2016). APOBEC3A/B-induced mutations, as well as mutations in mismatch repair (MMR)-deficient cells, are strongly biased toward the lagging strand (Lujan et al 2012;Andrianova et al 2016; …”

Section: Replication Asymmetry Of Tpcpw→k Mutations Is Not Due To Asymentioning

confidence: 99%

APOBEC3A/B-induced mutagenesis is responsible for 20% of heritable mutations in the TpCpW context

2016

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APOBEC3A/B cytidine deaminase is responsible for the majority of cancerous mutations in a large fraction of cancer samples. However, its role in heritable mutagenesis remains very poorly understood. Recent studies have demonstrated that both in yeast and in human cancerous cells, most APOBEC3A/B-induced mutations occur on the lagging strand during replication and on the nontemplate strand of transcribed regions. Here, we use data on rare human polymorphisms, interspecies divergence, and de novo mutations to study germline mutagenesis and to analyze mutations at nucleotide contexts prone to attack by APOBEC3A/B. We show that such mutations occur preferentially on the lagging strand and on nontemplate strands of transcribed regions. Moreover, we demonstrate that APOBEC3A/B-like mutations tend to produce strandcoordinated clusters, which are also biased toward the lagging strand. Finally, we show that the mutation rate is increased 3 ′ of C→G mutations to a greater extent than 3 ′ of C→T mutations, suggesting pervasive trans-lesion bypass of the APOBEC3A/B-induced damage. Our study demonstrates that 20% of C→T and C→G mutations in the TpCpW context-where W denotes A or T, segregating as polymorphisms in human population-or 1.4% of all heritable mutations are attributable to APOBEC3A/B activity.

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Replication Fork Polarity Gradients Revealed by Megabase-Sized U-Shaped Replication Timing Domains in Human Cell Lines

Cited by 71 publications

References 60 publications

Linking the DNA strand asymmetry to the spatio-temporal replication program

Linking the DNA strand asymmetry to the spatio-temporal replication program

Human mismatch repair system balances mutation rates between strands by removing more mismatches from the lagging strand

APOBEC3A/B-induced mutagenesis is responsible for 20% of heritable mutations in the TpCpW context

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