A minimal threshold of FANCJ helicase activity is required for its response to replication stress or double-strand break repair.
Nucleic Acids Res
; 46(12): 6238-6256, 2018 07 06.
Article
in En
| MEDLINE
| ID: mdl-29788478
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
DNA Helicases
/
RNA Helicases
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DNA Repair
/
DNA Replication
/
Fanconi Anemia Complementation Group Proteins
/
DNA Breaks, Double-Stranded
Limits:
Animals
Language:
En
Journal:
Nucleic Acids Res
Year:
2018
Document type:
Article
Affiliation country:
United States