Repair and tolerance of DNA damage at the replication fork: A structural perspective

Eichman, Brandt F.

doi:10.1016/j.sbi.2023.102618

Cited by 4 publications

(2 citation statements)

References 72 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cellular DNA is constantly exposed to both endogenous and exogenous insults, many of which damage the nitrogenous bases. In cells undergoing DNA replication, this base damage can cause replicative polymerases to pause during synthesis, stalling replication forks [1, 2]. Prolonged stalling results in disassembly of the replication machinery and, in severe situations, fork collapse, leading to one-ended DNA double-stranded breaks (DSBs).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

REV1 Coordinates a Multi-Faceted Tolerance Response to DNA Alkylation Damage and Prevents Chromosome Shattering inDrosophila melanogaster

Khodaverdian,

Sano,

Maggs

et al. 2024

Preprint

View full text Add to dashboard Cite

When replication forks encounter damaged DNA, cells utilize DNA damage tolerance mechanisms to allow replication to proceed. These include translesion synthesis at the fork, postreplication gap filling, and template switching via fork reversal or homologous recombination. The extent to which these different damage tolerance mechanisms are utilized depends on cell, tissue, and developmental context-specific cues, the last two of which are poorly understood. To address this gap, we have investigated damage tolerance responses following alkylation damage inDrosophila melanogaster. We report that translesion synthesis, rather than template switching, is the preferred response to alkylation-induced damage in diploid larval tissues. Furthermore, we show that the REV1 protein plays a multi-faceted role in damage tolerance in Drosophila. Drosophila larvae lacking REV1 are hypersensitive to methyl methanesulfonate (MMS) and have highly elevated levels of γ-H2Av foci and chromosome aberrations in MMS-treated tissues. Loss of the REV1 C-terminal domain (CTD), which recruits multiple translesion polymerases to damage sites, sensitizes flies to MMS. In the absence of the REV1 CTD, DNA polymerases eta and zeta become critical for MMS tolerance. In addition, flies lacking REV3, the catalytic subunit of polymerase zeta, require the deoxycytidyl transferase activity of REV1 to tolerate MMS. Together, our results demonstrate that Drosophila prioritize the use of multiple translesion polymerases to tolerate alkylation damage and highlight the critical role of REV1 in the coordination of this response to prevent genome instability.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

REV1 Coordinates a Multi-Faceted Tolerance Response to DNA Alkylation Damage and Prevents Chromosome Shattering inDrosophila melanogaster

Khodaverdian,

Sano,

Maggs

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

NEIL3 promoter G-quadruplex with oxidatively modified bases shows magnesium-dependent folding that stalls polymerase bypass

2023

View full text Add to dashboard Cite

Strand dependent bypass of DNA lesions during fork reversal by ATP-dependent translocases SMARCAL1, ZRANB3, and HLTF

Adolph,

Warren,

Couch

et al. 2024

Preprint

View full text Add to dashboard Cite

During DNA replication, the replisome encounters obstacles including DNA lesions, transcription-replication conflicts, and other sources of replication stress. These obstacles must be efficiently overcome to complete DNA synthesis and minimize genome instability. One pathway to tolerate replication stress is replication fork reversal, in which parental template DNA strands are reannealed and a nascent-nascent DNA duplex is formed. Several enzymes promote replication fork reversal, including the ATP-dependent translocases SMARCAL1, ZRANB3, and HLTF. How these enzymes translocate on DNA that contains fork-stalling lesions is unknown. Here, we examined the abilities of SMARCAL1, ZRANB3, and HLTF to tolerate various lesions on leading or lagging template strands. We demonstrate that SMARCAL1 and ZRANB3 are selectively inhibited by lesions on the leading template strand, whereas HLTF is insensitive to bulky lesions on either strand. These results suggest that SMARCAL1 and ZRANB3 contact the leading strand during fork reversal and therefore are more sensitive to inhibition by bulky lesions on this strand. In contrast, HLTF DNA translocation is inherently insensitive to DNA lesions. These biochemical differences between the fork reversal enzymes provide insights into their mechanism of DNA remodeling and suggest they may act in lesion-specific contexts.

show abstract

Repair and tolerance of DNA damage at the replication fork: A structural perspective

Cited by 4 publications

References 72 publications

REV1 Coordinates a Multi-Faceted Tolerance Response to DNA Alkylation Damage and Prevents Chromosome Shattering inDrosophila melanogaster

REV1 Coordinates a Multi-Faceted Tolerance Response to DNA Alkylation Damage and Prevents Chromosome Shattering inDrosophila melanogaster

NEIL3 promoter G-quadruplex with oxidatively modified bases shows magnesium-dependent folding that stalls polymerase bypass

Strand dependent bypass of DNA lesions during fork reversal by ATP-dependent translocases SMARCAL1, ZRANB3, and HLTF

Contact Info

Product

Resources

About