Mechanisms by which Human Cells Bypass Damaged Bases during DNA Replication after Ultraviolet Irradiation

The replication of damaged DNA involves cascading mechanisms of increasing complexity but decreasing accuracy. The most accurate mechanism uses low-fidelity DNA polymerases, Pol H and Pol I, which have active sites sufficiently large to accommodate a pyrimidine dimer. Replicative bypass of DNA damag...

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Main Author: James E. Cleaver
Format: Article
Language:English
Published: Wiley 2002-01-01
Series:The Scientific World Journal
Online Access:http://dx.doi.org/10.1100/tsw.2002.348
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author James E. Cleaver
author_facet James E. Cleaver
author_sort James E. Cleaver
collection DOAJ
description The replication of damaged DNA involves cascading mechanisms of increasing complexity but decreasing accuracy. The most accurate mechanism uses low-fidelity DNA polymerases, Pol H and Pol I, which have active sites sufficiently large to accommodate a pyrimidine dimer. Replicative bypass of DNA damage by these polymerases produces an accurately replicated, newly synthesized strand. Pol H negative cells (XP-V cell lines) either adopt a proposed secondary bypass mechanism or a recombinational mode. The mechanism of the secondary bypass is unclear, but a number of experiments suggests roles for excision repair to remove damage ahead of replication forks, hRad6/18 proteolysis to clear the blocked forks, and the Rad17-RFC and 9-1-1 complexes to establish a new replication apparatus. This alternative pathway requires functional p53. In Pol H negative cells in which p53 is also inactive, the arrested fork fragments into DNA double strand breaks. Foci containing PCNA, Mre11/Rad50/Nbs1, and gamma-H2Ax can then be detected, along with chromosomal rearrangement and high frequencies of sister chromatid exchanges. The recruitment of recombination components to the arrested forks represents the ultimate failure of replication machinery to relieve the arrested state and bypass the damage. The resulting chromosomal instability in surviving cells will contribute to malignant transformation.
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spelling doaj-art-9cfde9eb2487466d9800ce0ba01105082025-02-03T07:25:57ZengWileyThe Scientific World Journal1537-744X2002-01-0121296130510.1100/tsw.2002.348Mechanisms by which Human Cells Bypass Damaged Bases during DNA Replication after Ultraviolet IrradiationJames E. Cleaver0UCSF Cancer Center, University of California, San Francisco, USAThe replication of damaged DNA involves cascading mechanisms of increasing complexity but decreasing accuracy. The most accurate mechanism uses low-fidelity DNA polymerases, Pol H and Pol I, which have active sites sufficiently large to accommodate a pyrimidine dimer. Replicative bypass of DNA damage by these polymerases produces an accurately replicated, newly synthesized strand. Pol H negative cells (XP-V cell lines) either adopt a proposed secondary bypass mechanism or a recombinational mode. The mechanism of the secondary bypass is unclear, but a number of experiments suggests roles for excision repair to remove damage ahead of replication forks, hRad6/18 proteolysis to clear the blocked forks, and the Rad17-RFC and 9-1-1 complexes to establish a new replication apparatus. This alternative pathway requires functional p53. In Pol H negative cells in which p53 is also inactive, the arrested fork fragments into DNA double strand breaks. Foci containing PCNA, Mre11/Rad50/Nbs1, and gamma-H2Ax can then be detected, along with chromosomal rearrangement and high frequencies of sister chromatid exchanges. The recruitment of recombination components to the arrested forks represents the ultimate failure of replication machinery to relieve the arrested state and bypass the damage. The resulting chromosomal instability in surviving cells will contribute to malignant transformation.http://dx.doi.org/10.1100/tsw.2002.348
spellingShingle James E. Cleaver
Mechanisms by which Human Cells Bypass Damaged Bases during DNA Replication after Ultraviolet Irradiation
The Scientific World Journal
title Mechanisms by which Human Cells Bypass Damaged Bases during DNA Replication after Ultraviolet Irradiation
title_full Mechanisms by which Human Cells Bypass Damaged Bases during DNA Replication after Ultraviolet Irradiation
title_fullStr Mechanisms by which Human Cells Bypass Damaged Bases during DNA Replication after Ultraviolet Irradiation
title_full_unstemmed Mechanisms by which Human Cells Bypass Damaged Bases during DNA Replication after Ultraviolet Irradiation
title_short Mechanisms by which Human Cells Bypass Damaged Bases during DNA Replication after Ultraviolet Irradiation
title_sort mechanisms by which human cells bypass damaged bases during dna replication after ultraviolet irradiation
url http://dx.doi.org/10.1100/tsw.2002.348
work_keys_str_mv AT jamesecleaver mechanismsbywhichhumancellsbypassdamagedbasesduringdnareplicationafterultravioletirradiation