Eukaryotic Translesion DNA Synthesis on the Leading and Lagging Strands: Unique Detours around the Same Obstacle

Mark Hedglin, Stephen Benkovic

Research output: Contribution to journalReview article

16 Citations (Scopus)

Abstract

During S-phase, minor DNA damage may be overcome by DNA damage tolerance (DDT) pathways that bypass such obstacles, postponing repair of the offending damage to complete the cell cycle and maintain cell survival. In translesion DNA synthesis (TLS), specialized DNA polymerases replicate the damaged DNA, allowing stringent DNA synthesis by a replicative polymerase to resume beyond the offending damage. Dysregulation of this DDT pathway in human cells leads to increased mutation rates that may contribute to the onset of cancer. Furthermore, TLS affords human cancer cells the ability to counteract chemotherapeutic agents that elicit cell death by damaging DNA in actively replicating cells. Currently, it is unclear how this critical pathway unfolds, in particular, where and when TLS occurs on each template strand. Given the semidiscontinuous nature of DNA replication, it is likely that TLS on the leading and lagging strand templates is unique for each strand. Since the discovery of DDT in the late 1960s, most studies on TLS in eukaryotes have focused on DNA lesions resulting from ultraviolet (UV) radiation exposure. In this review, we revisit these and other related studies to dissect the step-by-step intricacies of this complex process, provide our current understanding of TLS on leading and lagging strand templates, and propose testable hypotheses to gain further insights.

Original languageEnglish (US)
Pages (from-to)7857-7877
Number of pages21
JournalChemical Reviews
Volume117
Issue number12
DOIs
StatePublished - Jun 28 2017

Fingerprint

DNA
Damage tolerance
Cells
Cell death
DNA-Directed DNA Polymerase
Ultraviolet radiation
Repair

All Science Journal Classification (ASJC) codes

  • Chemistry(all)

Cite this

@article{20a7ad0d59824ea0abc6b21e9cd20559,
title = "Eukaryotic Translesion DNA Synthesis on the Leading and Lagging Strands: Unique Detours around the Same Obstacle",
abstract = "During S-phase, minor DNA damage may be overcome by DNA damage tolerance (DDT) pathways that bypass such obstacles, postponing repair of the offending damage to complete the cell cycle and maintain cell survival. In translesion DNA synthesis (TLS), specialized DNA polymerases replicate the damaged DNA, allowing stringent DNA synthesis by a replicative polymerase to resume beyond the offending damage. Dysregulation of this DDT pathway in human cells leads to increased mutation rates that may contribute to the onset of cancer. Furthermore, TLS affords human cancer cells the ability to counteract chemotherapeutic agents that elicit cell death by damaging DNA in actively replicating cells. Currently, it is unclear how this critical pathway unfolds, in particular, where and when TLS occurs on each template strand. Given the semidiscontinuous nature of DNA replication, it is likely that TLS on the leading and lagging strand templates is unique for each strand. Since the discovery of DDT in the late 1960s, most studies on TLS in eukaryotes have focused on DNA lesions resulting from ultraviolet (UV) radiation exposure. In this review, we revisit these and other related studies to dissect the step-by-step intricacies of this complex process, provide our current understanding of TLS on leading and lagging strand templates, and propose testable hypotheses to gain further insights.",
author = "Mark Hedglin and Stephen Benkovic",
year = "2017",
month = "6",
day = "28",
doi = "10.1021/acs.chemrev.7b00046",
language = "English (US)",
volume = "117",
pages = "7857--7877",
journal = "Chemical Reviews",
issn = "0009-2665",
publisher = "American Chemical Society",
number = "12",

}

Eukaryotic Translesion DNA Synthesis on the Leading and Lagging Strands : Unique Detours around the Same Obstacle. / Hedglin, Mark; Benkovic, Stephen.

In: Chemical Reviews, Vol. 117, No. 12, 28.06.2017, p. 7857-7877.

Research output: Contribution to journalReview article

TY - JOUR

T1 - Eukaryotic Translesion DNA Synthesis on the Leading and Lagging Strands

T2 - Unique Detours around the Same Obstacle

AU - Hedglin, Mark

AU - Benkovic, Stephen

PY - 2017/6/28

Y1 - 2017/6/28

N2 - During S-phase, minor DNA damage may be overcome by DNA damage tolerance (DDT) pathways that bypass such obstacles, postponing repair of the offending damage to complete the cell cycle and maintain cell survival. In translesion DNA synthesis (TLS), specialized DNA polymerases replicate the damaged DNA, allowing stringent DNA synthesis by a replicative polymerase to resume beyond the offending damage. Dysregulation of this DDT pathway in human cells leads to increased mutation rates that may contribute to the onset of cancer. Furthermore, TLS affords human cancer cells the ability to counteract chemotherapeutic agents that elicit cell death by damaging DNA in actively replicating cells. Currently, it is unclear how this critical pathway unfolds, in particular, where and when TLS occurs on each template strand. Given the semidiscontinuous nature of DNA replication, it is likely that TLS on the leading and lagging strand templates is unique for each strand. Since the discovery of DDT in the late 1960s, most studies on TLS in eukaryotes have focused on DNA lesions resulting from ultraviolet (UV) radiation exposure. In this review, we revisit these and other related studies to dissect the step-by-step intricacies of this complex process, provide our current understanding of TLS on leading and lagging strand templates, and propose testable hypotheses to gain further insights.

AB - During S-phase, minor DNA damage may be overcome by DNA damage tolerance (DDT) pathways that bypass such obstacles, postponing repair of the offending damage to complete the cell cycle and maintain cell survival. In translesion DNA synthesis (TLS), specialized DNA polymerases replicate the damaged DNA, allowing stringent DNA synthesis by a replicative polymerase to resume beyond the offending damage. Dysregulation of this DDT pathway in human cells leads to increased mutation rates that may contribute to the onset of cancer. Furthermore, TLS affords human cancer cells the ability to counteract chemotherapeutic agents that elicit cell death by damaging DNA in actively replicating cells. Currently, it is unclear how this critical pathway unfolds, in particular, where and when TLS occurs on each template strand. Given the semidiscontinuous nature of DNA replication, it is likely that TLS on the leading and lagging strand templates is unique for each strand. Since the discovery of DDT in the late 1960s, most studies on TLS in eukaryotes have focused on DNA lesions resulting from ultraviolet (UV) radiation exposure. In this review, we revisit these and other related studies to dissect the step-by-step intricacies of this complex process, provide our current understanding of TLS on leading and lagging strand templates, and propose testable hypotheses to gain further insights.

UR - http://www.scopus.com/inward/record.url?scp=85021648998&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85021648998&partnerID=8YFLogxK

U2 - 10.1021/acs.chemrev.7b00046

DO - 10.1021/acs.chemrev.7b00046

M3 - Review article

C2 - 28497687

AN - SCOPUS:85021648998

VL - 117

SP - 7857

EP - 7877

JO - Chemical Reviews

JF - Chemical Reviews

SN - 0009-2665

IS - 12

ER -