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Article
| Open Access
Distinctive roles of translesion polymerases DinB1 and DnaE2 in diversification of the mycobacterial genome through substitution and frameshift mutagenesis
This manuscript elucidates new mechanisms of mutagenesis in mycobacteria by implicating two translesion DNA polymerases in genome diversification, including creating the mutations that underlie all antibiotic resistance in these global pathogens.
- Pierre Dupuy
- , Shreya Ghosh
- & Michael S. Glickman
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Article
| Open Access
Cryo-EM structure of translesion DNA synthesis polymerase ζ with a base pair mismatch
The structure of mismatched DNA-Polζ ternary complex provides a basis for understanding what makes Polζ adept at extending DNA synthesis past mismatched base pairs.
- Radhika Malik
- , Robert E. Johnson
- & Aneel K. Aggarwal
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Article
| Open Access
BRCA1 deficiency specific base substitution mutagenesis is dependent on translesion synthesis and regulated by 53BP1
Loss of BRCA1 or BRCA2 results in genomic instability; however most studies have focused on the role of these proteins in double-strand break repair. Here the authors coupled cell line genetics and whole genome sequencing to investigate the formation of base substitutions and short indels in BRCA1-deficient cells, revealing a role for translesion DNA synthesis regulated by 53BP1.
- Dan Chen
- , Judit Z. Gervai
- & Dávid Szüts
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Article
| Open Access
Structural basis of DNA synthesis opposite 8-oxoguanine by human PrimPol primase-polymerase
The human DNA primase and DNA polymerase PrimPol replicates through the major oxidative DNA damage lesion 7,8-dihydro-8-oxoguanine (oxoG) via translesion synthesis in a mostly error-free manner thus suppressing oxoG-induced mutagenesis in mitochondria and the nucleus. Here, the authors present crystal structures of PrimPol in complex with an oxoG lesion in different contexts that provide mechanistic insights into how PrimPol performs predominantly accurate synthesis on oxidative-damaged DNAs in human cells.
- Olga Rechkoblit
- , Robert E. Johnson
- & Aneel K. Aggarwal
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Article
| Open Access
REV7 is required for processing AID initiated DNA lesions in activated B cells
REV7 has emerged as a critical regulator of DNA double-strand breaks repair. Here, the authors show that REV7 is crucial for both antibody class switch recombination and somatic hypermutation in activated B cells, in addition to their survival upon AID-deamination.
- Dingpeng Yang
- , Ying Sun
- & Fei-Long Meng
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Article
| Open Access
Mutational signatures are jointly shaped by DNA damage and repair
Recent research has shown that mutational signatures reflective of the history of a cancer can be detected in a cancer genome. Here, using whole genome sequencing of DNA repair deficient and proficient nematodes exposed to genotoxins, the authors show that these mutational signatures reflect both the initial DNA damage that was inflicted and the repair processes that ensue.
- Nadezda V. Volkova
- , Bettina Meier
- & Moritz Gerstung
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Article
| Open Access
Single-molecule imaging reveals multiple pathways for the recruitment of translesion polymerases after DNA damage
Translesion synthesis (TLS) enables cells to tolerate damaged DNA encountered during replication. Here the authors use super-resolution photoactivation localization microscopy to reveal a lesion type dependent mechanism of recruitment of the TLS polymerase Pol IV following DNA damage.
- Elizabeth S. Thrall
- , James E. Kath
- & Joseph J. Loparo
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Article
| Open Access
Polη O-GlcNAcylation governs genome integrity during translesion DNA synthesis
Polη is a key player in translesion DNA synthesis. Here, the authors uncover that, in response to DNA damage, Polη undergoes O-GlcNAcylation at threonine 457 by O-GlcNAc transferase to facilitate the timely disassembly of Polη after DNA lesion bypass.
- Xiaolu Ma
- , Hongmei Liu
- & Caixia Guo
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Article
| Open Access
Rad18-dependent SUMOylation of human specialized DNA polymerase eta is required to prevent under-replicated DNA
Translesion synthesis polymerase eta has a well characterized role in replicating past UV-induced DNA lesions and has recently been shown to act at difficult to replicate sequences. Here the authors show that its SUMOylation is required to recruit pol eta at the replication fork and to prevent under-replicated DNA.
- Emmanuelle Despras
- , Méghane Sittewelle
- & Patricia L Kannouche
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Structure of p15PAF–PCNA complex and implications for clamp sliding during DNA replication and repair
p15PAF regulates DNA replication and repair via interactions with the Proliferating Cell Nuclear Antigen (PCNA) sliding clamp. Here the authors present multi-faceted structural analyses of the p15-PCNA-DNA complex that suggests p15 regulates the sliding of PCNA along DNA during replication.
- Alfredo De Biasio
- , Alain Ibáñez de Opakua
- & Francisco J. Blanco
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Article
| Open Access
Identification of novel DNA-damage tolerance genes reveals regulation of translesion DNA synthesis by nucleophosmin
Cells cope with replication-blocking DNA lesions by translesion DNA synthesis (TLS) polymerases, including polη. Here, the authors show that NPM1, a gene frequently mutated in acute myeloid leukaemia, protects polη from proteasomal degradation, and that NPM1 deficiency causes a TLS defect.
- Omer Ziv
- , Amit Zeisel
- & Zvi Livneh
MAD2L2 promotes replication fork protection and recovery in a shieldin-independent and REV3L-dependent manner