scholarly journals Nontranscriptional Function of FOXO1/DAF-16 Contributes to Translesion DNA Synthesis

2016 ◽  
Vol 36 (21) ◽  
pp. 2755-2766 ◽  
Author(s):  
Hiroaki Daitoku ◽  
Yuta Kaneko ◽  
Kenji Yoshimochi ◽  
Kaori Matsumoto ◽  
Sho Araoi ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Synthesis ◽  
Uv Irradiation ◽  
Protein A ◽  
Dna Lesions ◽  
Nuclear Antigen ◽  
Transactivation Domain ◽  
Content Type ◽  
Translesion Dna Synthesis ◽  
Translesion Dna

Forkhead box O (FOXO; DAF-16 in nematodes) transcription factors activate a program of genes that control stress resistance, metabolism, and life span. Given the adverse impact of the stochastic DNA damage on organismal development and aging, we examined the role of FOXO/DAF-16 in UV-induced DNA damage response. Knockdown of FOXO1 but not of FOXO3a increases sensitivity to UV irradiation when exposed during S phase, suggesting a contribution of FOXO1 to translesion DNA synthesis (TLS), a replicative bypass of UV-induced DNA lesions. Actually, FOXO1 depletion results in sustained activation of ATR-Chk1 signaling and a reduction of proliferating cell nuclear antigen (PCNA) monoubiquitination following UV irradiation. FOXO1 does not alter the expression of TLS-related genes, but it binds to replication protein A 1 (RPA1), which coats single-stranded DNA and acts as a scaffold for TLS. InCaenorhabditis elegans,daf-16-null mutants show UV-induced retardation in larval development and are rescued by overexpressing a DAF-16 mutant lacking the transactivation domain but not a mutant whose amino acid substitutions render it unable to interact with RPA1. Thus, our findings demonstrate that FOXO1/DAF-16 is a functional component in TLS independent of its transactivation activity.

scholarly journals A Single Domain in Human DNA Polymerase ι Mediates Interaction with PCNA: Implications for Translesion DNA Synthesis

2005 ◽  
Vol 25 (3) ◽  
pp. 1183-1190 ◽  
Author(s):  
Lajos Haracska ◽  
Narottam Acharya ◽  
Ildiko Unk ◽  
Robert E. Johnson ◽  
Jerard Hurwitz ◽  
...  
Keyword(s):  
Dna Synthesis ◽  
Tight Binding ◽  
Dna Lesions ◽  
Nuclear Antigen ◽  
Binding Motifs ◽  
Translesion Dna Synthesis ◽  
Nucleotide Incorporation ◽  
Y Family ◽  
Stalled Replication Forks ◽  
Proliferating Cell

ABSTRACT DNA polymerases (Pols) of the Y family rescue stalled replication forks by promoting replication through DNA lesions. Humans have four Y family Pols, η, ι, κ, and Rev1, of which Pols η, ι, and κ have been shown to physically interact with proliferating cell nuclear antigen (PCNA) and be functionally stimulated by it. However, in sharp contrast to the large increase in processivity that PCNA binding imparts to the replicative Pol, Polδ, the processivity of Y family Pols is not enhanced upon PCNA binding. Instead, PCNA binding improves the efficiency of nucleotide incorporation via a reduction in the apparent Km for the nucleotide. Here we show that Polι interacts with PCNA via only one of its conserved PCNA binding motifs, regardless of whether PCNA is bound to DNA or not. The mode of PCNA binding by Polι is quite unlike that in Polδ, where multisite interactions with PCNA provide for a very tight binding of the replicating Pol with PCNA. We discuss the implications of these observations for the accuracy of DNA synthesis during translesion synthesis and for the process of Pol exchange at the lesion site.

scholarly journals Division of labor of Y-family polymerases in translesion-DNA synthesis for distinct types of DNA damage

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0252587
Author(s):  
Yuriko Inomata ◽  
Takuya Abe ◽  
Masataka Tsuda ◽  
Shunichi Takeda ◽  
Kouji Hirota
Keyword(s):  
Dna Damage ◽  
Dna Synthesis ◽  
Division Of Labor ◽  
Double Knockout ◽  
Translesion Dna Synthesis ◽  
Translesion Dna ◽  
Template Dna ◽  
Y Family ◽  
Higher Sensitivity

Living organisms are continuously under threat from a vast array of DNA-damaging agents, which impact genome DNA. DNA replication machinery stalls at damaged template DNA. The stalled replication fork is restarted via bypass replication by translesion DNA-synthesis polymerases, including the Y-family polymerases Polη, Polι, and Polκ, which possess the ability to incorporate nucleotides opposite the damaged template. To investigate the division of labor among these polymerases in vivo, we generated POLη−/−, POLι−/−, POLκ−/−, double knockout (KO), and triple knockout (TKO) mutants in all combinations from human TK6 cells. TKO cells exhibited a hypersensitivity to ultraviolet (UV), cisplatin (CDDP), and methyl methanesulfonate (MMS), confirming the pivotal role played by these polymerases in bypass replication of damaged template DNA. POLη−/− cells, but not POLι−/− or POLκ−/− cells, showed a strong sensitivity to UV and CDDP, while TKO cells showed a slightly higher sensitivity to UV and CDDP than did POLη−/− cells. On the other hand, TKO cells, but not all single KO cells, exhibited a significantly higher sensitivity to MMS than did wild-type cells. Consistently, DNA-fiber assay revealed that Polη plays a crucial role in bypassing lesions caused by UV-mimetic agent 4-nitroquinoline-1-oxide and CDDP, while all three polymerases play complementary roles in bypassing MMS-induced damage. Our findings indicate that the three Y-family polymerases play distinctly different roles in bypass replication, according to the type of DNA damage generated on the template strand.

scholarly journals Structure of a Mutant Form of Proliferating Cell Nuclear Antigen That Blocks Translesion DNA Synthesis†‡

Biochemistry ◽  
2008 ◽  
Vol 47 (50) ◽  
pp. 13354-13361 ◽  
Author(s):  
Bret D. Freudenthal ◽  
S. Ramaswamy ◽  
Manju M. Hingorani ◽  
M. Todd Washington
Keyword(s):  
Dna Synthesis ◽  
Proliferating Cell Nuclear Antigen ◽  
Nuclear Antigen ◽  
Mutant Form ◽  
Translesion Dna Synthesis ◽  
Translesion Dna ◽  
Proliferating Cell

scholarly journals Stimulation of DNA Synthesis Activity of Human DNA Polymerase κ by PCNA

2002 ◽  
Vol 22 (3) ◽  
pp. 784-791 ◽  
Author(s):  
Lajos Haracska ◽  
Ildiko Unk ◽  
Robert E. Johnson ◽  
Barbara B. Phillips ◽  
Jerard Hurwitz ◽  
...  
Keyword(s):  
Dna Synthesis ◽  
Dna Polymerases ◽  
Protein A ◽  
Dna Lesions ◽  
Nuclear Antigen ◽  
Physical Interaction ◽  
Abasic Site ◽  
Nucleotide Incorporation ◽  
Synthesis Activity ◽  
Factor C

ABSTRACT Humans have three DNA polymerases, Polη, Polκ, and Polι, which are able to promote replication through DNA lesions. However, the mechanism by which these DNA polymerases are targeted to the replication machinery stalled at a lesion site has remained unknown. Here, we provide evidence for the physical interaction of human Polκ (hPolκ) with proliferating cell nuclear antigen (PCNA) and show that PCNA, replication factor C (RFC), and replication protein A (RPA) act cooperatively to stimulate the DNA synthesis activity of hPolκ. The processivity of hPolκ, however, is not significantly increased in the presence of these protein factors. The efficiency (V max/K m ) of correct nucleotide incorporation by hPolκ is enhanced ∼50- to 200-fold in the presence of PCNA, RFC, and RPA, and this increase in efficiency is achieved by a reduction in the apparent K m for the nucleotide. Although in the presence of these protein factors, the efficiency of the insertion of an A nucleotide opposite an abasic site is increased ∼40-fold, this reaction still remains quite inefficient; thus, it is unlikely that hPolκ would bypass an abasic site by inserting a nucleotide opposite the site.

scholarly journals PIDD orchestrates translesion DNA synthesis in response to UV irradiation

2011 ◽  
Vol 18 (6) ◽  
pp. 1036-1045 ◽  
Author(s):  
E Logette ◽  
S Schuepbach-Mallepell ◽  
M J Eckert ◽  
X H Leo ◽  
B Jaccard ◽  
...  
Keyword(s):  
Dna Synthesis ◽  
Uv Irradiation ◽  
Translesion Dna Synthesis ◽  
Translesion Dna

scholarly journals Archaeal replicative primases can perform translesion DNA synthesis

2015 ◽  
Vol 112 (7) ◽  
pp. E633-E638 ◽  
Author(s):  
Stanislaw K. Jozwiakowski ◽  
Farimah Borazjani Gholami ◽  
Aidan J. Doherty
Keyword(s):  
Dna Synthesis ◽  
Uv Light ◽  
Small Subunit ◽  
Dna Lesions ◽  
Cyclobutane Pyrimidine Dimers ◽  
Translesion Dna Synthesis ◽  
Template Strand ◽  
Pyrimidine Dimers ◽  
Translesion Dna ◽  
Y Family

DNA replicases routinely stall at lesions encountered on the template strand, and translesion DNA synthesis (TLS) is used to rescue progression of stalled replisomes. This process requires specialized polymerases that perform translesion DNA synthesis. Although prokaryotes and eukaryotes possess canonical TLS polymerases (Y-family Pols) capable of traversing blocking DNA lesions, most archaea lack these enzymes. Here, we report that archaeal replicative primases (Pri S, primase small subunit) can also perform TLS. Archaeal Pri S can bypass common oxidative DNA lesions, such as 8-Oxo-2'-deoxyguanosines and UV light-induced DNA damage, faithfully bypassing cyclobutane pyrimidine dimers. Although it is well documented that archaeal replicases specifically arrest at deoxyuracils (dUs) due to recognition and binding to the lesions, a replication restart mechanism has not been identified. Here, we report that Pri S efficiently replicates past dUs, even in the presence of stalled replicase complexes, thus providing a mechanism for maintaining replication bypass of these DNA lesions. Together, these findings establish that some replicative primases, previously considered to be solely involved in priming replication, are also TLS proficient and therefore may play important roles in damage tolerance at replication forks.

scholarly journals PDIP38/PolDIP2 controls the DNA damage tolerance pathways by increasing the relative usage of translesion DNA synthesis over template switching

PLoS ONE ◽  
2019 ◽  
Vol 14 (3) ◽  
pp. e0213383 ◽  
Author(s):  
Masataka Tsuda ◽  
Saki Ogawa ◽  
Masato Ooka ◽  
Kaori Kobayashi ◽  
Kouji Hirota ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Synthesis ◽  
Damage Tolerance ◽  
Template Switching ◽  
Dna Damage Tolerance ◽  
Translesion Dna Synthesis ◽  
Translesion Dna
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