A minimal threshold of FANCJ helicase activity is required for its response to replication stress or double-strand break repair

Sanjay Kumar Bharti, Joshua A. Sommers, Sanket Awate, Marina A. Bellani, Irfan Khan, Lynda Bradley, Graeme A. King, Yeonee Seol, Venkatasubramanian Vidhyasagar, Yuliang Wu, Takuye Abe, Koji Kobayashi, Kazuo Shin-Ya, Hiroyuki Kitao, Marc S. Wold, Dana Branzei, Keir C. Neuman, Robert M. Brosh

研究成果: Contribution to journalArticle査読

11 被引用数 (Scopus)

抄録

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.

本文言語英語
ページ(範囲)6238-6256
ページ数19
ジャーナルNucleic acids research
46
12
DOI
出版ステータス出版済み - 7 6 2018

All Science Journal Classification (ASJC) codes

  • Genetics

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