PDIP38/PolDIP2 controls the DNA damage tolerance pathways by increasing the relative usage of translesion DNA synthesis over template switching.
Animals
Avian Proteins
/ deficiency
Cell Line
Chickens
DNA
/ biosynthesis
DNA Damage
DNA Polymerase beta
/ deficiency
DNA Primase
/ deficiency
DNA Repair
DNA Replication
DNA-Directed DNA Polymerase
/ deficiency
Gene Knockout Techniques
Genes, Immunoglobulin
Humans
Multifunctional Enzymes
/ deficiency
Nuclear Proteins
/ deficiency
Templates, Genetic
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2019
2019
Historique:
received:
03
10
2018
accepted:
19
02
2019
entrez:
7
3
2019
pubmed:
7
3
2019
medline:
18
12
2019
Statut:
epublish
Résumé
Replicative DNA polymerases are frequently stalled at damaged template strands. Stalled replication forks are restored by the DNA damage tolerance (DDT) pathways, error-prone translesion DNA synthesis (TLS) to cope with excessive DNA damage, and error-free template switching (TS) by homologous DNA recombination. PDIP38 (Pol-delta interacting protein of 38 kDa), also called Pol δ-interacting protein 2 (PolDIP2), physically associates with TLS DNA polymerases, polymerase η (Polη), Polλ, and PrimPol, and activates them in vitro. It remains unclear whether PDIP38 promotes TLS in vivo, since no method allows for measuring individual TLS events in mammalian cells. We disrupted the PDIP38 gene, generating PDIP38-/- cells from the chicken DT40 and human TK6 B cell lines. These PDIP38-/- cells did not show a significant sensitivity to either UV or H2O2, a phenotype not seen in any TLS-polymerase-deficient DT40 or TK6 mutants. DT40 provides a unique opportunity of examining individual TLS and TS events by the nucleotide sequence analysis of the immunoglobulin variable (Ig V) gene as the cells continuously diversify Ig V by TLS (non-templated Ig V hypermutation) and TS (Ig gene conversion) during in vitro culture. PDIP38-/- cells showed a shift in Ig V diversification from TLS to TS. We measured the relative usage of TLS and TS in TK6 cells at a chemically synthesized UV damage (CPD) integrated into genomic DNA. The loss of PDIP38 also caused an increase in the relative usage of TS. The number of UV-induced sister chromatid exchanges, TS events associated with crossover, was increased a few times in PDIP38-/- human and chicken cells. Collectively, the loss of PDIP38 consistently causes a shift in DDT from TLS to TS without enhancing cellular sensitivity to DNA damage. We propose that PDIP38 controls the relative usage of TLS and TS increasing usage of TLS without changing the overall capability of DDT.
Identifiants
pubmed: 30840704
doi: 10.1371/journal.pone.0213383
pii: PONE-D-18-28757
pmc: PMC6402704
doi:
Substances chimiques
Avian Proteins
0
Multifunctional Enzymes
0
Nuclear Proteins
0
POLDIP2 protein, human
0
DNA
9007-49-2
DNA Primase
EC 2.7.7.-
DNA polymerase beta2
EC 2.7.7.-
PrimPol protein, human
EC 2.7.7.-
DNA Polymerase beta
EC 2.7.7.7
DNA-Directed DNA Polymerase
EC 2.7.7.7
Rad30 protein
EC 2.7.7.7
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0213383Subventions
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/H019723/1
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/M008800/1
Pays : United Kingdom
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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