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Review
. 2024 Jan 1;436(1):168275.
doi: 10.1016/j.jmb.2023.168275. Epub 2023 Sep 13.

Role of Translesion DNA Synthesis in the Metabolism of Replication-associated Nascent Strand Gaps

Jude B Khatib  1 , Claudia M Nicolae  2 , George-Lucian Moldovan  3
Affiliations
Review

Role of Translesion DNA Synthesis in the Metabolism of Replication-associated Nascent Strand Gaps

Jude B Khatib et al. J Mol Biol. .

Abstract

Translesion DNA synthesis (TLS) is a DNA damage tolerance pathway utilized by cells to overcome lesions encountered throughout DNA replication. During replication stress, cancer cells show increased dependency on TLS proteins for cellular survival and chemoresistance. TLS proteins have been described to be involved in various DNA repair pathways. One of the major emerging roles of TLS is single-stranded DNA (ssDNA) gap-filling, primarily after the repriming activity of PrimPol upon encountering a lesion. Conversely, suppression of ssDNA gap accumulation by TLS is considered to represent a mechanism for cancer cells to evade the toxicity of chemotherapeutic agents, specifically in BRCA-deficient cells. Thus, TLS inhibition is emerging as a potential treatment regimen for DNA repair-deficient tumors.

Keywords: BRCA; homologous recombination; replication stress; ssDNA gaps; translesion synthesis.

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Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Figure 1.
Figure 1.. DNA Damage tolerance pathways.
As a result of DNA-damaging agents and replication stress, replication forks arrest at fork blocking obstacles. Various repair pathways can be utilized by the cell for survival. Created with BioRender.com.
Figure 2.
Figure 2.. Roles of TLS in DNA repair.
A. Mechanism of lesion bypass by TLS, also referred to as “TLS on the Fly”. Upon the encounter of a lesion, PCNA is ubiquitinated by the RAD6-RAD18 ligase complex, initiating the switch to a TLS polymerase. USP1 acts as a major regulator of TLS after lesion bypass. B. Repriming after a lesion by PrimPol leaves behind ssDNA gaps that are either filled by homology-dependent repair or by TLS. BRCA status may dictate the choice of gap-filling mechanism. Created with BioRender.com.
Figure 3.
Figure 3.. Repair of ssDNA gaps drives chemoresistance in BRCA-deficient cells.
BRCA-proficient cells are able to survive the toxicity of chemotherapeutic agents by utilizing homology-dependent repair. However, BRCA-deficient cells are sensitive to such therapies through the accumulation of ssDNA gaps. These can cells develop resistance by relying on TLS for gap repair and survival. Created with BioRender.com.
See this image and copyright information in PMC

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