2021
DOI: 10.1093/nar/gkab1223
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Translesion DNA synthesis-driven mutagenesis in very early embryogenesis of fast cleaving embryos

Abstract: In early embryogenesis of fast cleaving embryos, DNA synthesis is short and surveillance mechanisms preserving genome integrity are inefficient, implying the possible generation of mutations. We have analyzed mutagenesis in Xenopus laevis and Drosophila melanogaster early embryos. We report the occurrence of a high mutation rate in Xenopus and show that it is dependent upon the translesion DNA synthesis (TLS) master regulator Rad18. Unexpectedly, we observed a homology-directed repair contribution of Rad18 in … Show more

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Cited by 4 publications
(2 citation statements)
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“…Considering that N 2 -alkyl-dG can be induced from by-products of endogenous metabolism and that Pol κ-mediated nucleotide insertion opposite these lesions is both accurate and efficient ( 9 , 10 ), active engagement of Pol κ in replicating genomic regions early in the S phase may minimize mutation accumulation from endogenously induced DNA lesions. Our findings, together with the documented roles of Pol η and Pol ξ in heterochromatin replication ( 6 , 8 ), are consistent with the needs of mutation avoidance in actively transcribed genes replicated early in the S phase, while allowing for genome evolution in late-replicating heterochromatin regions ( 8 ). Hence, our work expands the functions of Pol κ and offers a plausible mechanism underlying the diminished mutation rates detected in these regions of the cancer genomes ( 2 ).…”
Section: Discussionsupporting
confidence: 86%
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“…Considering that N 2 -alkyl-dG can be induced from by-products of endogenous metabolism and that Pol κ-mediated nucleotide insertion opposite these lesions is both accurate and efficient ( 9 , 10 ), active engagement of Pol κ in replicating genomic regions early in the S phase may minimize mutation accumulation from endogenously induced DNA lesions. Our findings, together with the documented roles of Pol η and Pol ξ in heterochromatin replication ( 6 , 8 ), are consistent with the needs of mutation avoidance in actively transcribed genes replicated early in the S phase, while allowing for genome evolution in late-replicating heterochromatin regions ( 8 ). Hence, our work expands the functions of Pol κ and offers a plausible mechanism underlying the diminished mutation rates detected in these regions of the cancer genomes ( 2 ).…”
Section: Discussionsupporting
confidence: 86%
“…Translesion synthesis (TLS) is a conserved mechanism for cells to cope with unrepaired DNA lesions by promoting replication across DNA lesions ( 3 ). Recent studies also documented noncanonical functions of these polymerases, including DNA repair ( 4 ), replicative bypass of secondary structures of DNA, e.g., guanine quadruplex DNA ( 5 ), as well as replication of common fragile sites and heterochromatin ( 6 8 ). Pol κ is a Y-family TLS polymerase, and it is conserved throughout evolution ( 3 ).…”
mentioning
confidence: 99%