FANCJ Helicase Uniquely Senses Oxidative Base Damage in Either Strand of Duplex DNA and Is Stimulated by Replication Protein A to Unwind the Damaged DNA Substrate in a Strand-specific Manner

Avvaru N Suhasini; Joshua A Sommers; Aaron C Mason; Oleg N Voloshin; R. Daniel Camerini-Otero; Marc S Wold; Robert M Brosh

doi:10.1074/jbc.M109.012229

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FANCJ Helicase Uniquely Senses Oxidative Base Damage in Either Strand of Duplex DNA and Is Stimulated by Replication Protein A to Unwind the Damaged DNA Substrate in a Strand-specific Manner

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FANCJ Helicase Uniquely Senses Oxidative Base Damage in Either Strand of Duplex DNA and Is Stimulated by Replication Protein A to Unwind the Damaged DNA Substrate in a Strand-specific Manner

Avvaru N Suhasini, Joshua A Sommers, Aaron C Mason, Oleg N Voloshin, R. Daniel Camerini-Otero, Marc S Wold and Robert M Brosh

The Journal of biological chemistry, Vol.284(27), pp.18458-18470

07/03/2009

DOI: 10.1074/jbc.M109.012229

PMCID: PMC2709400

PMID: 19419957

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Abstract

FANCJ mutations are genetically linked to the Fanconi anemia complementation group J and predispose individuals to breast cancer. Understanding the role of FANCJ in DNA metabolism and how FANCJ dysfunction leads to tumorigenesis requires mechanistic studies of FANCJ helicase and its protein partners. In this work, we have examined the ability of FANCJ to unwind DNA molecules with specific base damage that can be mutagenic or lethal. FANCJ was inhibited by a single thymine glycol, but not 8-oxoguanine, in either the translocating or nontranslocating strands of the helicase substrate. In contrast, the human RecQ helicases (BLM, RECQ1, and WRN) display strand-specific inhibition of unwinding by the thymine glycol damage, whereas other DNA helicases (DinG, DnaB, and UvrD) are not significantly inhibited by thymine glycol in either strand. In the presence of replication protein A (RPA), but not Escherichia coli single-stranded DNA-binding protein, FANCJ efficiently unwound the DNA substrate harboring the thymine glycol damage in the nontranslocating strand; however, inhibition of FANCJ helicase activity by the translocating strand thymine glycol was not relieved. Strand-specific stimulation of human RECQ1 helicase activity was also observed, and RPA bound with high affinity to single-stranded DNA containing a single thymine glycol. Based on the biochemical studies, we propose a model for the specific functional interaction between RPA and FANCJ on the thymine glycol substrates. These studies are relevant to the roles of RPA, FANCJ, and other DNA helicases in the metabolism of damaged DNA that can interfere with basic cellular processes of DNA metabolism.

DNA

Repair, Recombination, and Chromosome Dynamics

Details

Title: Subtitle: FANCJ Helicase Uniquely Senses Oxidative Base Damage in Either Strand of Duplex DNA and Is Stimulated by Replication Protein A to Unwind the Damaged DNA Substrate in a Strand-specific Manner
Creators: Avvaru N Suhasini - From the
Joshua A Sommers - From the
Aaron C Mason - the
Oleg N Voloshin - the
R. Daniel Camerini-Otero - the
Marc S Wold - the
Robert M Brosh - From the
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.284(27), pp.18458-18470
DOI: 10.1074/jbc.M109.012229
PMID: 19419957
PMCID: PMC2709400
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: American Society for Biochemistry and Molecular Biology; 9650 Rockville Pike, Bethesda, MD 20814, U.S.A
Grant note: GM44721 / National Institutes of Health
Language: English
Date published: 07/03/2009
Academic Unit: Radiation Oncology; Biochemistry and Molecular Biology
Record Identifier: 9984024530802771

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