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A minimal threshold of FANCJ helicase activity is required for its response to replication stress or double-strand break repair
- Source :
- Nucleic Acids Research
- Publication Year :
- 2018
- Publisher :
- Oxford University Press, 2018.
-
Abstract
- Fanconi Anemia (FA) is characterized by bone marrow failure, congenital abnormalities, and cancer. Of over 20 FA-linked genes, FANCJ uniquely encodes a DNA helicase and mutations are also associated with breast and ovarian cancer. fancj−/− cells are sensitive to DNA interstrand cross-linking (ICL) and replication fork stalling drugs. We delineated the molecular defects of two FA patient-derived FANCJ helicase domain mutations. FANCJ-R707C was compromised in dimerization and helicase processivity, whereas DNA unwinding by FANCJ-H396D was barely detectable. DNA binding and ATP hydrolysis was defective for both FANCJ-R707C and FANCJ-H396D, the latter showing greater reduction. Expression of FANCJ-R707C or FANCJ-H396D in fancj−/− cells failed to rescue cisplatin or mitomycin sensitivity. Live-cell imaging demonstrated a significantly compromised recruitment of FANCJ-R707C to laser-induced DNA damage. However, FANCJ-R707C expressed in fancj-/- cells conferred resistance to the DNA polymerase inhibitor aphidicolin, G-quadruplex ligand telomestatin, or DNA strand-breaker bleomycin, whereas FANCJ-H396D failed. Thus, a minimal threshold of FANCJ catalytic activity is required to overcome replication stress induced by aphidicolin or telomestatin, or to repair bleomycin-induced DNA breakage. These findings have implications for therapeutic strategies relying on DNA cross-link sensitivity or heightened replication stress characteristic of cancer cells.
- Subjects :
- 0301 basic medicine
Aphidicolin
DNA Replication
DNA Repair
DNA damage
DNA repair
Mutation, Missense
DNA, Single-Stranded
Cell Line
Recombinases
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Stress, Physiological
Replication Protein A
Genetics
Animals
DNA Breaks, Double-Stranded
Replication protein A
Oxazoles
Adenosine Triphosphatases
biology
Nucleic Acid Enzymes
DNA replication
DNA Helicases
Helicase
Processivity
Fanconi Anemia Complementation Group Proteins
Cell biology
G-Quadruplexes
030104 developmental biology
Fanconi Anemia
chemistry
030220 oncology & carcinogenesis
Checkpoint Kinase 1
biology.protein
DNA Polymerase Inhibitor
Rad51 Recombinase
Cisplatin
Chickens
RNA Helicases
Subjects
Details
- Language :
- English
- ISSN :
- 13624962 and 03051048
- Volume :
- 46
- Issue :
- 12
- Database :
- OpenAIRE
- Journal :
- Nucleic Acids Research
- Accession number :
- edsair.doi.dedup.....54d6341d4f0e3bdc90a2bb28debbeb29